System for non-invasive measurement of an analyte in a vehicle driver

ABSTRACT

A system for non-invasively measuring an analyte in a vehicle driver and controlling a vehicle based on a measurement of the analyte. At least one solid-state light source is configured to emit different wavelengths of light. A sample device is configured to introduce the light emitted by the at least one solid-state light source into tissue of the vehicle driver. One or more optical detectors are configured to detect a portion of the light that is not absorbed by the tissue of the vehicle driver. A controller is configured to calculate a measurement of the analyte in the tissue of the vehicle driver based on the light detected by the one or more optical detectors, determine whether the measurement of the analyte in the tissue of the vehicle driver exceeds a pre-determined value, and provide a signal to a device configured to control the vehicle.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority from U.S. Provisional Application61/528,658, filed Aug. 29, 2011, incorporated herein by reference in itsentirety.

BACKGROUND

The present application generally relates to a system and methods fornon-invasively measuring an analyte in a vehicle driver. Morespecifically, the application relates to a measurement quantitativespectroscopy system for measuring the presence or concentration of ananalyte, for example, alcohol, alcohol byproducts, alcohol adducts, orsubstances of abuse, utilizing non-invasive techniques in combinationwith multivariate analysis.

Current practice for alcohol measurements is based upon either bloodmeasurements or breath testing. Blood measurements define the goldstandard for determining alcohol intoxication levels. However, bloodmeasurements require either a venous or capillary sample and involvesignificant handling precautions in order to minimize health risks. Onceextracted, the blood sample must be properly labeled and transported toa clinical laboratory or other suitable location where a clinical gaschromatograph is typically used to measure the blood alcohol level. Dueto the invasiveness of the procedure and the amount of sample handlinginvolved, blood alcohol measurements are usually limited to criticalsituations such as for traffic accidents, violations where the suspectrequests this type of test, and accidents where injuries are involved.

Because it is less invasive, breath testing is more commonly encounteredin the field. In breath testing, the subject must expire air into theinstrument for a sufficient time and volume to achieve a stable breathflow that originates from the alveoli deep within the lungs. The devicethen measures the alcohol content in the air, which is related to bloodalcohol through a breath-blood partition coefficient. The blood-breathpartition coefficient used in the United States is 2100 (implied unitsof mg EtOH/dL blood per mg EtOH/dL air) and varies between 1900 and 2400in other nations. The variability in the partition coefficient is due tothe fact that it is highly subject dependent. In other words, eachsubject will have a partition coefficient in the 1900 to 2400 range thatdepends on his or her physiology. Since knowledge of each subject'spartition coefficient is unavailable in field applications, each nationassumes a single partition coefficient value that is globally applied toall measurements. In the U.S., defendants in DUI cases often use theglobally applied partition coefficient as an argument to impedeprosecution.

Breath measurements have additional limitations. First, the presence of“mouth alcohol” can falsely elevate the breath alcohol measurement. Thisnecessitates a 15-minute waiting period prior to making a measurement inorder to ensure that no mouth alcohol is present. For a similar reason,a 15 minute delay is required for individuals who are observed to burpor vomit. A delay of 10 minutes or more is often required between breathmeasurements to allow the instrument to return to equilibrium with theambient air and zero alcohol levels. In addition, the accuracy of breathalcohol measurements is sensitive to numerous physiological andenvironmental factors.

Multiple government agencies, and society in general, seek non-invasivealternatives to blood and breath alcohol measurements. Quantitativespectroscopy offers the potential for a completely non-invasive alcoholmeasurement that is not sensitive to the limitations of the currentmeasurement methodologies. While non-invasive determination ofbiological attributes by quantitative spectroscopy has been found to behighly desirable, it has been very difficult to accomplish. Attributesof interest include, as examples, analyte presence, analyteconcentration (e.g., alcohol concentration), direction of change of ananalyte concentration, rate of change of an analyte concentration,disease presence (e.g., alcoholism), disease state, and combinations andsubsets thereof. Non-invasive measurements via quantitative spectroscopyare desirable because they are painless, do not require a fluid drawfrom the body, carry little risk of contamination or infection, do notgenerate any hazardous waste, and can have short measurement times.

Several systems have been proposed for the non-invasive determination ofattributes of biological tissue. These systems have includedtechnologies incorporating polarimetry, mid-infrared spectroscopy, Ramanspectroscopy, Kromoscopy, fluorescence spectroscopy, nuclear magneticresonance spectroscopy, radio-frequency spectroscopy, ultrasound,transdermal measurements, photo-acoustic spectroscopy, and near-infraredspectroscopy. However, these systems have not replaced direct andinvasive measurements.

As an example, Robinson et al. in U.S. Pat. No. 4,975,581 disclose amethod and apparatus for measuring a characteristic of unknown value ina biological sample using infrared spectroscopy in conjunction with amultivariate model that is empirically derived from a set of spectra ofbiological samples of known characteristic values. The above-mentionedcharacteristic is generally the concentration of an analyte, such asalcohol, but also can be any chemical or physical property of thesample. The method of Robinson et al. involves a two-step process thatincludes both calibration and prediction steps.

In the calibration step, the infrared light is coupled to calibrationsamples of known characteristic values so that there is attenuation ofat least several wavelengths of the infrared radiation as a function ofthe various components and analytes comprising the sample with knowncharacteristic value. The infrared light is coupled to the sample bypassing the light through the sample or by reflecting the light off thesample. Absorption of the infrared light by the sample causes intensityvariations of the light that are a function of the wavelength of thelight. The resulting intensity variations at a minimum of severalwavelengths are measured for the set of calibration samples of knowncharacteristic values. Original or transformed intensity variations arethen empirically related to the known characteristics of the calibrationsamples using multivariate algorithms to obtain a multivariatecalibration model. The model preferably accounts for subjectvariability, instrument variability, and environment variability.

In the prediction step, the infrared light is coupled to a sample ofunknown characteristic value, and a multivariate calibration model isapplied to the original or transformed intensity variations of theappropriate wavelengths of light measured from this unknown sample. Theresult of the prediction step is the estimated value of thecharacteristic of the unknown sample. The disclosure of Robinson et al.is incorporated herein by reference.

A further method of building a calibration model and using such modelfor prediction of analytes and/or attributes of tissue is disclosed incommonly assigned U.S. Pat. No. 6,157,041 to Thomas et al., entitled“Method and Apparatus for Tailoring Spectrographic Calibration Models,”the disclosure of which is incorporated herein by reference.

In U.S. Pat. No. 5,830,112, Robinson describes a general method ofrobust sampling of tissue for non-invasive analyte measurement. Thesampling method utilizes a tissue-sampling accessory that is pathlengthoptimized by spectral region for measuring an analyte such as alcohol.The patent discloses several types of spectrometers for measuring thespectrum of the tissue from 400 to 2500 nm, including acousto-opticaltunable filters, discrete wavelength spectrometers, filters, gratingspectrometers and FTIR spectrometers. The disclosure of Robinson isincorporated herein by reference.

Although there has been substantial work conducted in attempting toproduce commercially viable non-invasive near-infraredspectroscopy-based systems for determination of biological attributes,no such device is presently available. It is believed that prior artsystems discussed above have failed for one or more reasons to fullymeet the challenges imposed by the spectral characteristics of tissuewhich make the design of a non-invasive measurement system a formidabletask. Thus, there is a substantial need for a commercially viable devicewhich incorporates subsystems and methods with sufficient accuracy andprecision to make clinically relevant determinations of biologicalattributes in human tissue.

SUMMARY

One embodiment of the invention relates to a system for non-invasivelymeasuring an analyte in a vehicle driver and controlling a vehicle basedon a measurement of the analyte. The system includes at least onesolid-state light source, a sample device, one or more optical detectorsand a controller. The at least one solid-state light source isconfigured to emit different wavelengths of light. The sample device isconfigured to introduce the light emitted by the at least onesolid-state light source into tissue of the vehicle driver. The one ormore optical detectors are configured to detect a portion of the lightthat is not absorbed by the tissue of the vehicle driver. The controlleris configured to calculate a measurement of the analyte in the tissue ofthe vehicle driver based on the light detected by the one or moreoptical detectors, determine whether the measurement of the analyte inthe tissue of the vehicle driver exceeds a pre-determined value, andprovide a signal to a device configured to control the vehicle.

Another embodiment of the invention relates to a method fornon-invasively measuring an analyte in a vehicle driver and controllinga vehicle based on a measurement of the analyte. A sample deviceintroduces different wavelengths of light emitted by at least onesolid-state light source into tissue of the vehicle driver. One or moreoptical detectors detect a portion of the light that is not absorbed bythe tissue of the vehicle driver. A controller calculates a measurementof the analyte in the tissue of the vehicle driver based on the lightdetected by the one or more optical detectors. The controller determineswhether the measurement of the analyte in the tissue of the vehicledriver exceeds a pre-determined value and controls the vehicle based onthe measurement of the analyte in the tissue of the vehicle driver.

Additional features, advantages, and embodiments of the presentdisclosure may be set forth from consideration of the following detaileddescription, drawings, and claims. Moreover, it is to be understood thatboth the foregoing summary of the present disclosure and the followingdetailed description are exemplary and intended to provide furtherexplanation without further limiting the scope of the present disclosureclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate preferred embodiments of theinvention and together with the description serve to explain principlesof the invention. No attempt is made to show structural details of thepresent disclosure in more detail than may be necessary for afundamental understanding of the present disclosure and the various waysin which it may be practiced.

FIG. 1 is a schematic depiction of a non-invasive spectrometer systemincorporating the disclosed subsystems.

FIG. 2 is a graphical depiction of the concept of net attribute signalin a three-component system.

FIG. 3 is an embodiment of an electronic circuit designed to control thedrive current of a solid-state light source including means for turningthe light source on and off.

FIG. 4 is an embodiment of an electronic circuit designed to control thedrive current of a solid-state light source including means for turningthe light source on and off and altering the desired drive current.

FIG. 5 is an embodiment of the Illumination/Modulation Subsystemcomprising multiple individual solid-state light sources arranged in anarray whose outputs are introduced to a hexagonal cross sectioninternally reflective light homogenizer.

FIG. 6 is an embodiment of a single laser emitter in a semiconductorchip.

FIG. 7 is an embodiment of the Illumination/Modulation Subsystem wheremultiple laser emitters are mounted to a common carrier.

FIG. 8 is an embodiment of the Illumination/Modulation Subsystem thatdepicts a laser bar comprised of a single semiconductor chip thatcontains 24 emitters (12 different wavelengths, 2 emitters perwavelength).

FIG. 9 is a schematic view of an embodiment of a fiber optic couplerthat collects light emitted from each pair of emitters in the laser barembodiment shown in FIG. 8 and combines the individual optical fibersinto an output bundle or cable.

FIG. 10 is an embodiment that combines the outputs of 4 different fibercouplers into a single output aperture/bundle, where each couple isconnected to a different laser bar.

FIG. 11 is an example embodiment of a light homogenizer suitable forhomogenizing the light from the illumination/modulation subsystem'soutput aperture/bundle.

FIG. 12 is a perspective view of elements of a tissue samplingsubsystem.

FIG. 13 is a plan view of the sampling surface of the tissue samplingsubsystem, showing an arrangement of illumination and collection opticalfibers.

FIG. 14 is an alternative embodiment of the sampling surface of thetissue sampling subsystem.

FIG. 15 is an alternative embodiment of the sampling surface of thetissue sampling subsystem.

FIG. 16 is an alternative embodiment of the sampling surface of thetissue sampling subsystem that is optimized for the small emission areaof some solid-state light source based Illumination/ModulationSubsystems.

FIG. 17 is a diagramed view of the interface between the samplingsurface and the tissue when topical interferents are present on thetissue.

FIG. 18 is a schematic representation of the data acquisition subsystem.

FIG. 19 is a diagram of the hybrid calibration formation process.

FIG. 20 demonstrates the effectiveness of multivariate calibrationoutlier metrics for detecting the presence of topical interferents.

FIG. 21 shows normalized NIR spectra of 1300 and 3000 K blackbodyradiators over the 100-33000 cm¹ (100-0.3 μm) range.

FIG. 22 shows a schematic of the components of an exemplary embodimentof the present invention.

FIG. 23 depicts noninvasive tissue spectra acquired using 22wavelengths.

FIG. 24 compares noninvasive tissue alcohol concentrations obtained fromthe spectra in FIG. 23 to contemporaneous capillary blood alcoholconcentration.

FIG. 25 depicts noninvasive tissue spectra acquired using 39wavelengths.

FIG. 26 compares noninvasive tissue alcohol concentrations obtained fromthe spectra in FIG. 25 to contemporaneous capillary blood alcoholconcentration.

FIG. 27 depicts one of many possible embodiment of a measurementtimeline including system calibration, measurement, and counter measurestime zones.

FIG. 28 depicts a non-invasive monitoring system incorporated as avehicle starter button in a vehicle instrument panel.

FIG. 29a depicts a side view of a non-invasive measurement portalinterface where the emitter is a wavelength homogenizer directlyconnected to wavelength light sources.

FIG. 29b depicts a top view of the non-invasive measurement portalinterface of FIG. 29a where the emitter is a wavelength homogenizerdirectly connected to wavelength light sources.

FIG. 30 depicts the components of a non-invasive monitoring system whichutilizes a broadly tunable laser emitter to provide a means forspectrally separated absorption measurements.

FIG. 31 depicts one of many possible embodiment of a measurementtimeline to improve the average required measurement time where theinitial measurement detects the existence of an analyte, and asubsequent measurement is made to determine the actual concentration ofthe analyte.

FIG. 32 depicts a non-invasive monitoring system where the primaryanalyte measurement is made through a touch system and a secondarymeasurement is made through an alternative analyte detection system.

FIG. 33 depicts the components of a non-invasive monitoring system whichutilizes a blackbody light source with filter elements to provide theselection of discrete wavelengths to compose the emitted light source.

FIG. 34 depicts the intensity of a light source during transition froman off state to an on state time of measurement is made prior tointensity settling.

DETAILED DESCRIPTION

Before turning to the figures, which illustrate the exemplaryembodiments in detail, it should be understood that the presentdisclosure is not limited to the details or methodology set forth in thedescription or illustrated in the figures. It should also be understoodthat the terminology is for the purpose of description only and shouldnot be regarded as limiting. An effort has been made to use the same orlike reference numbers throughout the drawings to refer to the same orlike parts.

For the purposes of the present application, the term “analyteconcentration” generally refers to the concentration of an analyte, suchas alcohol. The term “analyte property” includes analyte concentrationand other properties, such as the presence or absence of the analyte orthe direction or rate of change of the analyte concentration, or abiometric, which can be measured in conjunction with or instead of theanalyte concentration. While the disclosure generally references alcoholas the “analyte” of interest, other analytes, including but not limitedto substances of abuse, alcohol biomarkers, and alcohol byproducts, arealso intended to be covered by the systems and methods disclosed in thepresent application. The term “alcohol” is used as an example analyte ofinterest; the term is intended to include ethanol, methanol, ethylglycol or any other chemical commonly referred to as alcohol. For thepurposes of this application, the term “alcohol byproducts” includes theadducts and byproducts of the metabolism of alcohol by the bodyincluding, but not limited to, acetone, acetaldehyde, and acetic acid.The term “alcohol biomarkers” includes, but is not limited to, GammaGlutamyl Transferase (GGT), Aspartate Amino Transferase (AST), AlanineAmino Transferase (ALT), Mean Corpuscular Volume (MCV),Carbohydrate-Deficient Transferrin (CDT), Ethyl Glucuronide (EtG), EthylSulfate (EtS), and Phosphatidyl Ethanol (PEth). The term “substances ofabuse” refers to, but is not limited to, THC (Tetrahydrocannabinol ormarijuana), cocaine, M-AMP (methamphetamine), OPI (morphine and heroin),OxyContin, Oxycodone, and PCP (phencyclidine). The term “biometric”refers to an analyte or biological characteristic that can be used toidentify or verify the identity of a specific person or subject. Thepresent application discloses systems and methods that address the needfor analyte measurements of samples utilizing spectroscopy where theterm “sample” generally refers to biological tissue. The term “subject”generally refers to a person from whom a sample measurement wasacquired.

The terms “solid-state light source” or “semiconductor light source”refer to all sources of light, whether spectrally narrow (e.g. a laser)or broad (e.g. an LED) that are based upon semiconductors which include,but are not limited to, light emitting diodes (LED's), vertical cavitysurface emitting lasers (VCSEL's), horizontal cavity surface emittinglasers (HCSEL's), quantum cascade lasers, quantum dot lasers, diodelasers, or other semiconductor diodes or lasers. The term “diode laser”refers to any laser where the active medium is based on a semiconductorwhich include, but are not limited to, double heterostructure lasers,quantum well lasers, quantum cascade lasers, separate confinementheterostructure lasers, distributed feedback (DFB) lasers, VCSEL's,VECSEL's, HCSEL's, external-cavity diode lasers, Fabry-Perot lasers.Furthermore, plasma light sources and organic LED's, while not strictlybased on semiconductors, are also contemplated in the embodiments of thepresent invention and are thus included under the solid-state lightsource and semiconductor light source definitions for the purposes ofthis application.

For the purposes of this application the term “dispersive spectrometer”indicates a spectrometer based upon any device, component, or group ofcomponents that spatially separate one or more wavelengths of light fromother wavelengths. Examples include, but are not limited to,spectrometers that use one or more diffraction gratings, prisms,holographic gratings. For the purposes of this application the term“interferometric/modulating spectrometer” indicates a class ofspectrometers based upon the optical modulation of different wavelengthsof light to different frequencies in time or selectively transmits orreflects certain wavelengths of light based upon the properties of lightinterference. Examples include, but are not limited to, Fouriertransform interferometers, Sagnac interferometers, mock interferometers,Michelson interferometers, one or more etalons, or acousto-opticaltunable filters (AOTF's). One skilled in the art recognizes thatspectrometers based on combinations of dispersive andinterferometric/modulating properties, such as those based on lamellargratings, are also contemplated as being used with the systems andmethods disclosed in the present application.

The present application discloses the use of “signals” in some of theexamples as absorbance or other spectroscopic measurements. Signals cancomprise any measurement obtained concerning the spectroscopicmeasurement of a sample or change in a sample, e.g., absorbance,reflectance, intensity of light returned, fluorescence, transmission,Raman spectra, or various combinations of measurements, at one or morewavelengths. Some embodiments make use of one or more models, where sucha model can be anything that relates a signal to the desired property.Some examples of models include those derived from multivariate analysismethods, such as partial least squares regression (PLS), linearregression, multiple linear regression (MLR), classical least squaresregression (CLS), neural networks, discriminant analysis, principalcomponents analysis (PCA), principal components regression (PCR),discriminant analysis, neural networks, cluster analysis, and K-nearestneighbors. Single or multi-wavelength models based on the Beer-Lambertlaw are special cases of classical least squares and are thus includedin the term multivariate analysis for the purposes of the presentapplication.

For the purposes of the application, the term “about” applies to allnumeric values, whether or not explicitly indicated. The term “about”generally refers to a range of numbers that one of skill in the artwould consider equivalent to the recited value (i.e., having the samefunction or result). In some instances, the term “about” can includenumbers that are rounded to the nearest significant figure.

Spectroscopic measurement systems typically require some means forresolving and measuring different wavelengths of light in order toobtain a spectrum. Some common approaches achieve the desired spectruminclude dispersive (e.g. grating and prism based) spectrometers andinterferometric (e.g. Michelson, Sagnac, or other interferometer)spectrometers. Noninvasive measurement systems that incorporate suchapproaches are often limited by the expensive nature of dispersive andinterferometric devices as well as their inherent size, fragility, andsensitivity to environmental effects. The present application disclosessystems and methods that can provide an alternative approach forresolving and recording the intensities of different wavelengths usingsolid-state light sources such as light emitting diodes (LED's),vertical cavity surface emitting lasers (VCSEL's), horizontal cavitysurface emitting lasers (VCSEL's), diode lasers, quantum cascade lasers,or other solid-state light sources.

Referring generally to the figures, the disclosed system overcomes thechallenges posed by the spectral characteristics of tissue byincorporating a design that includes, in some embodiments, optimizedsubsystems. The design contends with the complexities of the tissuespectrum, high signal-to-noise ratio and photometric accuracyrequirements, tissue sampling errors, calibration maintenance problems,calibration transfer problems plus a host of other issues. Thesubsystems can include an illumination/modulation subsystem, a tissuesampling subsystem, a data acquisition subsystem, a computing subsystem,and a calibration subsystem.

An apparatus and method for non-invasive determination of attributes ofhuman tissue by quantitative near infrared spectroscopy is disclosedherein. The system includes subsystems optimized to contend with thecomplexities of the tissue spectrum, high signal-to-noise ratio andphotometric accuracy requirements, tissue sampling errors, calibrationmaintenance problems, and calibration transfer problems. The subsystemsinclude an illumination/modulation subsystem, a tissue samplingsubsystem, a data acquisition subsystem, and a computing subsystem.

The present application further discloses apparatus and methods thatallow for implementation and integration of each of these subsystems inorder to maximize the net attribute signal-to-noise ratio. The netattribute signal is the portion of the near-infrared spectrum that isspecific for the attribute of interest because it is orthogonal to allother sources of spectral variance. The orthogonal nature of the netattribute signal makes it perpendicular to the space defined by anyinterfering species and as a result, the net attribute signal isuncorrelated to these sources of variance. The net attributesignal-to-noise ratio is directly related to the accuracy and precisionfor non-invasive determination of the attribute by quantitativenear-infrared spectroscopy.

The present application discloses the use of near-infrared radiation foranalysis. Radiation in the wavelength range of 1.0 to 2.5 microns (orwavenumber range of 10,000 to 4,000 cm⁻¹) can be suitable for makingsome non-invasive measurements because such radiation has acceptablespecificity for a number of analytes, including alcohol, along withtissue optical penetration depths of up to several millimeters withacceptable absorbance characteristics. In the 1.0 to 2.5 micron spectralregion, the large number of optically active substances that make up thetissue complicate the measurement of any given substance due to theoverlapped nature of their absorbance spectra. Multivariate analysistechniques can be used to resolve these overlapped spectra such thataccurate measurements of the substance of interest can be achieved.Multivariate analysis techniques, however, can require that multivariatecalibrations remain robust over time (calibration maintenance) and beapplicable to multiple instruments (calibration transfer). Otherwavelength regions, such as the visible and infrared, can also besuitable for the disclosed systems and methods.

The present application discloses a multidisciplinary approach to thedesign of a spectroscopic instrument that incorporates an understandingof the instrument subsystems, tissue physiology, multivariate analysis,near-infrared spectroscopy and overall system operation. Further, theinteractions between the subsystems have been analyzed so that thebehavior and requirements for the entire non-invasive measurement deviceare well understood and result in a design for a commercial instrumentthat will make non-invasive measurements with sufficient accuracy andprecision at a price and size that is commercially viable.

The present application also discloses systems and methods for use withthe unique sensing requirements for a transportation systems includingbut not limited to motorcycles, automobiles, trucks, ships, trains andaircraft; where the system must operate over a wide range oftemperature, atmospheric pressure, altitudes, humidity, mechanicalorientation, ambient lighting and environmental constituent (e.g. salt,sand, dust, smoke) environments. The disclosed system may operate over afull range of potential users distinguishable through differences inweight, stature, age, ethnicity, gender, health, fitness level and otherhuman distinguishing factors. The disclosed system may remain functionalover a full vehicle life and maintain diagnostics and telltalesindicating required maintenance or serviceable unit replacement. Thedisclosed system can provide a human machine interface which providesvisual, haptic, audible feedback to inform the system user of a correctand incorrect measurement. The system provides diagnostics and userfeedback indicating proper and improper measurements including detectionof intentional and un-intentional system tampering or measurementspoofing. The system can maintain operational modes which can beenabled/disabled based on administrative controls (e.g. passwords). Thesystem can provide one or more communication and/or power interfaces toexternal transportation enabling or human machine interface systemsusing one or more existing or developed communication protocols toreceive data and/or power required for system operation or to enable,disable or modify the operation of the external systems. The system cansupport the capability to allow for measurement accuracy and precisionverification or calibration during manufacturing, installation and/orservice through a prosthetic reference device.

The subsystems of the non-invasive monitor are highly optimized toprovide reproducible and, preferably, uniform radiance of the tissue,low tissue sampling error, depth targeting of the tissue layers thatcontain the property of interest, efficient collection of diffusereflectance spectra from the tissue, high optical throughput, highphotometric accuracy, large dynamic range, excellent thermal stability,effective calibration maintenance, effective calibration transfer,built-in quality control, and ease-of-use.

Referring now to FIG. 1, a non-invasive monitor that is able to achieveacceptable levels of accuracy and precision for analyte propertymeasurements is depicted in schematic view. The overall systems can beviewed for discussion purposes as comprising five subsystems; thoseskilled in the art will appreciate other subdivisions of thefunctionality disclosed. The subsystems include anillumination/modulation subsystem 100, a tissue sampling subsystem 200,a data acquisition subsystem 300, a processing subsystem 400, and acalibration subsystem (not illustrated).

The subsystems can be designed and integrated in order to achieve adesirable net attribute signal-to-noise ratio. The net attribute signalis the portion of the near-infrared spectrum that is specific for theattribute of interest because it is orthogonal to other sources ofspectral variance. FIG. 2 is a graphical representation of the netattribute signal in a three dimensional system. The net attributesignal-to-noise ratio is directly related to the accuracy and precisionof the non-invasive attribute determination by quantitativenear-infrared spectroscopy.

The subsystems provide reproducible and preferably spatially uniformradiance of the tissue, low tissue sampling error, depth targeting ofappropriate layers of the tissue, efficient collection of diffusereflectance spectra from the tissue, high optical throughput, highphotometric accuracy, large dynamic range, excellent thermal stability,effective calibration maintenance, effective calibration transfer,built-in quality control and ease-of-use. Each of the subsystems isdiscussed below in more detail.

Illumination/Modulation Subsystem

The illumination/modulation subsystem 100 generates the light used tointerrogate the sample (e.g. skin tissue of a human). In classicalspectroscopy using dispersive or interferometric spectrometers, thespectrum of a polychromatic light source (or light emitted from a sampleof interest) is measured either by dispersing the different wavelengthsof light spatially (e.g. using a prism or a diffraction grating) or bymodulating different wavelengths of light to different frequencies (e.g.using a Michelson interferometer). In these cases, a spectrometer (asubsystem distinct from the light source) is required to perform thefunction of “encoding” different wavelengths either spatially or in timesuch that each can be measured substantially independently of otherwavelengths. While dispersive and interferometric spectrometers areknown in the art and can adequately serve their function in someenvironments and applications, they can be limited by their cost, size,fragility, signal to noise ratio (SNR), and complexity in otherapplications and environments.

An advantage of solid-state light sources incorporated in the disclosedsystems is that the sources can be independently modulated in intensity.Thus, multiple solid-state light sources that emit different wavelengthsof light can be used with each solid-state light source modulated at adifferent frequency or collectively modulated according to a predefinedscheme such as those defined by a Hadamard or similar approach. Theindependently modulated solid-state light sources can be opticallycombined into a single beam and introduced to the sample. A portion ofthe light can be collected from the sample and measured by a singlephotodetector. The result is the effective combination of thesolid-state light source and the spectrometer into a singleillumination/modulation subsystem that can offer significant benefits insize, cost, energy consumption, and overall system stability since thespectrometer, as an independent subsystem, is eliminated from themeasurement system. Furthermore, as all wavelengths are independentlymodulated and can be combined into a single beam, a single elementphotodetector (rather than an array of photodetectors) is suitable todetect all analytical light. This can represent a significant reductionin system complexity and cost relative to systems and embodiments withmultiple photodetector elements.

Several parameters of systems for measuring analyte propertiesincorporating solid-state light sources must be considered including,but not limited to, the number of solid-state light sources required toperform the desired measurement, the emission profile of the solid-statelight sources (e.g. spectral width, intensity), solid-state light sourcestability and control, and their optical combination. As eachsolid-state light source is a discrete element, it can be advantageousto combine the output of multiple solid-state light sources into asingle beam such that they are consistently introduced and collectedfrom the sample.

Furthermore, the modulation scheme for the solid-state light sourcesmust also be considered as some types of sources can be amenable tosinusoidal modulations in intensity where others can be amenable tobeing switched on and off or square wave modulated. In the case ofsinusoidal modulation, multiple solid-state light sources can bemodulated at different frequencies based on the electronics design ofthe system. The light emitted by the multiple sources can be opticallycombined, for example using a light pipe or other homogenizer,introduced and collected from the sample of interest, and then measuredby a single detector. The resulting signal can be converted into anintensity versus wavelength spectrum via a Fourier, or similar,transform.

Alternatively, some solid-state light sources are switched between theon and off state or square wave modulated which are amenable to aHadamard transform approach. However, in some embodiments, rather than atraditional Hadamard mask that blocks or passes different wavelengths atdifferent times during a measurement, the Hadamard scheme can beimplemented in electronics as solid-state light sources can be cycled athigh frequencies. A Hadamard or similar transform can be used todetermine the intensity versus wavelength spectrum. One skilled in theart recognizes that there are alternatives to Hadamard encodingapproaches that are equally suitable to the present invention.

In one embodiment, a 47 wavelength Hadamard encoding scheme is utilizedand depicted as a matrix of binary numbers. Each row corresponds to onestate of the Hadamard scheme and each column corresponds to a wavelengthin the measurement system. For each state, a value of “1” indicates thatwavelength (e.g. laser diode) is on for that state while a value of “0”indicates that wavelength is off for that state. Each measurement ofeach state corresponds to one scan. The light emitted by theIllumination/Modulation Subsystem 100 is delivered to the sample by theSampling Subsystem 200. A portion of that light is collected, detected,digitized, and recorded by the photodetector in the Data AcquisitionSubsystem 300. The next state in the Hadamard scheme (e.g. a differentset of wavelengths is on for that state) is then measured and recorded.This proceeds until all Hadamard states have been measured (referred toas a “Hadamard Cycle” herein). Once a Hadamard cycle has been completed,the intensity versus wavelength spectrum is determined by calculatingthe dot product of the recorded intensity versus state data and thematrix inverse of the Hadamard scheme. While the example of Hadamardencoding described above is comprised of 47 wavelengths, one skilled inthe art recognizes that Hadamard schemes with other numbers ofwavelengths are equally suitable for the present invention.

Another advantage of solid-state light sources is that many types (e.g.Laser diodes and VCSEL's) emit a narrow range of wavelengths (which inpart determines the effective resolution of the measurement).Consequently, shaping or narrowing the emission profile of solid-statelight sources with optical filters or other approaches is not requiredas they are already sufficiently narrow. This can be advantageous due todecreased system complexity and cost. Furthermore, the emissionwavelengths of some solid-state light sources, such as diode lasers andVCSEL's, are tunable over a range of wavelengths via either the supplieddrive current, drive voltage, or by changing the temperature of thesolid-state light source. The advantage of this approach is that if agiven measurement requires a specific number of wavelengths, the systemcan achieve the requirement with fewer discrete solid-state lightsources by tuning them over their feasible ranges. For example, ifmeasurement of a noninvasive property required twenty wavelengths, tendiscrete diode lasers or VCSEL's might be used with each of the tenbeing tuned to two different wavelengths during the course of ameasurement. In this type of scheme, a Fourier or Hadamard approachremains appropriate by changing the modulation frequency for each tuningpoint of a solid-state light source or by combining the modulationscheme with a scanning scheme. Furthermore, if the wavelength ofemission for a given laser drifts or changes over time, the tuningproperties of the diode laser allow it to be returned to its targetwavelength of emission by changing its drive current/voltage,temperature, or a combination thereof.

Analyte properties can be measured at a variety of wavelengths spanningthe ultraviolet and infrared regions of the electromagnetic spectrum.For in vivo measurements in skin, such as alcohol or substances ofabuse, the near infrared (NIR) region of 1,000 nm to 2,500 nm region canbe important due to the sensitivity and specificity of the spectroscopicsignals for the analyte of interest as well as other chemical species(e.g. water) that are present in human skin. Furthermore, theabsorptivities of the analytes are low enough that the near infraredlight can penetrate a few millimeters into the skin where the analytesof interest reside. The 2,000 nm to 2,500 nm wavelength range can be ofparticular utility as it contains combination bands rather than theweaker, less distinct overtones encountered in the 1,000 to 2,000 nmportion of the NIR.

In addition to the commonly available LED's, VCSEL's, and diode lasersin the visible region of the spectrum, there are solid-state lightsources available with emission wavelengths throughout the NIR region(1,000 to 2,500 nm). These solid-state light sources are suitable forthe disclosed analyte and biometric property measurement systems. Someexamples of available NIR solid-state light sources that are VCSEL'sproduced by Vertilas GmbH, and the VCSEL's, quantum cascade lasers,laser diodes available from Laser Components GmbH, or lasers and diodesavailable from Roithner Laser, Sacher Lasertechnik, NanoPlus,Mitsubishi, Epitex, Dora Texas Corporation, Microsensor Tech, SciTechInstruments, Laser 2000, Redwave Labs, and Deep Red Tech. These examplesare included for demonstrative purposes and are not intended to belimiting of the types of solid-state light sources suitable for use withthe present invention.

A microcontroller cab be used to control each solid-state light sourcein an embodiment of the illumination/modulation subsystem 100. Themicrocontroller can be programmed to include the defined states in theHadamard or other encoding scheme (e.g. the individual solid-state lightsources are turned off and on according to the set of states defined bythe scheme). The microcontroller can then cycle through each of thestates with a predetermined measurement time at each state. There is norestriction that the measurement time of each state must be equal. Inaddition to “off” and “on” control of each solid-state light source, themicrocontroller can also provide global (across all solid-state lightsources) and individual set points for solid-state light sourcetemperature and drive current/voltage. Such embodiments enablecontrolled wavelength tuning and/or improved stability of theillumination/modulation subsystem 100. One skilled in the art recognizesalternatives to microcontrollers are available that serve thesubstantially the same function as the described microcontrollerembodiments.

Measurement Resolution and Resolution Enhancement

In a dispersive spectrometer the effective resolution of a spectroscopicmeasurement is often determined by the width of an aperture in thesystem. The resolution limiting aperture is often the width of theentrance slit. At the focal plane where light within the spectrometer isdetected, multiple images of the slit are formed, with differentwavelengths located at different spatial locations on the focal plane.Thus, the ability to detect one wavelength independent of its neighborsis dependent on the width of the slit. Narrower widths allow betterresolution between wavelengths at the expense of the amount of lightthat can be passed through the spectrometer. Consequently, resolutionand signal to noise ratio generally trade against each other.Interferometric spectrometers have a similar trade between resolutionand signal to noise ratio. In the case of a Michelson interferometer theresolution of the spectrum is in part determined by the distance overwhich a moving mirror is translated with longer distances resulting ingreater resolution. The consequence is that the greater the distance,the more time is required to complete a scan.

In the case of the measurement systems, the resolution of the spectrumis determined by the spectral width of each of the discrete solid-statelight sources (whether a different solid-state light source, one tunedto multiple wavelengths, or a combination thereof). For measurements ofanalyte properties requiring high resolution, a diode laser or othersuitable solid state laser can be used. The widths of the laser'semission can be very narrow, which translates into high resolution. Inmeasurement applications where moderate to low resolution are required,LED's can be suitable as they typically have wider emission profiles(the output intensity is distributed across a wider range ofwavelengths) than solid state laser alternatives.

The effective resolution of solid-state light sources can be enhancedthrough the use, or combination of, different types of optical filters.The spectral width of a solid-state light source can be narrowed orattenuated using one or more optical filters in order to achieve higherresolution (e.g. a tighter range of emitted wavelengths). Examples ofoptical filters that are contemplated in embodiments of the presentinvention include, but are not limited to: linearly variable filters(LVF's), dielectric stacks, distributed Bragg gratings, photonic crystallattice filters, polymer films, absorption filters, reflection filters,etalons, dispersive elements such as prisms and gratings, and quantumdot filters.

Another means for improving the resolution of measurements obtained fromembodiments of the present invention is deconvolution. Deconvolution,and other similar approaches, can be used to isolate the signaldifference that is present between two or more overlapping broadsolid-state light sources. For example, two solid-state light sourceswith partially overlapping emission profiles can be incorporated into ameasurement system. A measurement can be acquired from a sample and aspectrum generated (via a Hadamard, Fourier transform, or other suitabletransform). With knowledge of the emission profiles of the solid-statelight sources, the profiles can be deconvolved from the spectrum inorder to enhance the resolution of the spectrum.

Stabilization and Control of Solid-State Light Source Wavelength andIntensity

The peak emission wavelength of solid-state light sources, particularlylasers, can be influenced by changing the thermal state or electricalproperties (e.g. drive current or voltage) of the solid-state lightsource. In the case of semiconductor lasers, changing the thermal stateand electrical properties alters the optical properties or physicaldimensions of the lattice structure of the semiconductor. The result isa change in the cavity spacing within the device, which alters the peakwavelength emitted. Since solid-state light sources exhibit theseeffects, when they are used in spectroscopic measurement systems thestability of the peak wavelength of emission and its associatedintensity can be important parameters. Consequently, during ameasurement control of both the thermal state and electrical propertiesof each solid-state light source can be advantageous in terms of overallsystem robustness and performance. Furthermore, the change in opticalproperties caused by thermal state and electrical conditions can beleveraged to allow a single solid-state light source to be tuned tomultiple peak wavelength locations. This can result in analyte propertymeasurement systems that can measure more wavelength locations than thenumber of discrete solid-state light sources which can reduce systemcost and complexity.

Temperature stabilization can be achieved using multiple approaches. Insome embodiments, a solid-state light source or solid-state lightsources can be stabilized by raising the temperature above (or coolingbelow) ambient conditions with no additional control of the temperature.In other embodiments, the solid-state light source or solid-state lightsources can be actively controlled to a set temperature (either cooledor heated) using a control loop. For example, a temperature loop circuitsuitable for an embodiment of the present invention may include aTE-Cooled VCSEL Package including a thermo-electric cooler and aprecision thermistor. The precision thermistor may be connected to aWheatstone bridge, which may be connected to a current drive circuitconfigured to drive the thermo-electric cooler.

The electrical properties of solid-state light sources also influencethe emission profile (e.g. wavelength locations of emission) ofsolid-state light sources. It can be advantageous to stabilize thecurrent and/or voltage supplied to the solid-state light source orsolid-state light sources. For example, the peak emission of VCSEL's andmany diode lasers depend on drive current. For embodiments where thestability of the peak wavelength is important, the stability of thedrive current becomes an important figure of merit. In such cases, anelectronic circuit can be designed to supply a stable drive current tothe VCSEL or diode laser. The complexity and cost of the circuit candepend on the required stability of the drive current. FIG. 3 shows acurrent drive circuit suitable for use with an embodiment of the presentinvention. One skilled in the art recognizes that alternativeembodiments of current control circuits are known in the art and canalso be suitable for the present invention. Furthermore, somesolid-state light sources require control of the drive voltage, ratherthan drive current; one skilled in the art recognizes that electronicscircuits designed to control voltage rather than current are readilyavailable.

In some embodiments, a single solid-state light source, such as a VCSELor diode laser, is tuned to multiple wavelengths during the course of ameasurement. In order to achieve the tuning of the solid-state lightsources, the circuit shown in FIG. 3 can be modified to include thecontrol of the temperature set point and current, respectively. In someembodiments, either tuning temperature or drive current/voltage can besufficient to realize the desired tuning of the peak emissionwavelength. In other embodiments, control of both the temperature anddrive current/voltage can be required to achieve the desired tuningrange.

Furthermore, optical means for measuring and stabilizing the peakemission wavelength can also be incorporated into the systems describedin connection with embodiments of the present invention. A Fabry-Perotetalon can be used to provide a relative wavelength standard. The freespectral range and finesse of the etalon can be specified to provide anoptical pass band that allows active measurement and control of theVCSEL or diode laser peak wavelength. An example embodiment of thisetalon uses a thermally stabilized, flat fused-silica plate withpartially mirrored surfaces. For systems where each VCSEL or diode laseris required to provide multiple wavelengths, the free spectral range ofthe etalon can be chosen such that its transmission peaks coincide withthe desired wavelength spacing for tuning. One skilled in the art willrecognize that there are many optical configurations and electroniccontrol circuits that are viable for this application. An alternatewavelength encoding scheme uses a dispersive grating and a secondaryarray detector to encode the VCSEL or diode laser wavelength into aspatial location on the array. For either the dispersive or the etalonbased schemes, a secondary optical detector that has less stringentperformance requirements than the main optical detector can be used.Active control can reduce the stability requirements of the VCSELtemperature and current control circuits by allowing real timecorrection for any drift.

Embodiments and Approaches for Multi-Wavelength Illumination/ModulationSubsystems

FIG. 5 shows an example embodiment of the Illumination/Modulationsubsystem 100 where 10 individual solid-state light sources 101 arearranged in a planar array. In some embodiments of FIG. 5, thesolid-state light sources 101 are individually housed in their ownpackages such as TO-9, TO-56, or other standard packages. These packagescan be sealed with transmissive windows or unsealed. In otherembodiments, the solid-state light sources 101 can be placed onto acommon carrier and the resulting assembly placed into a housing. Thehousing can be sealed or unsealed. The temperature of each solid-statelight source 101 can be controlled independently, where each solid-statelight source 101 has its own means for controlling temperature, orcollectively using a single means for controlling temperature.

The light emitted by the solid-state light sources 101 is collected andhomogenized by the homogenizer 102 (FIG. 5) and delivered to the inputof the Sampling Subsystem 200. In some embodiments of the presentinvention, the packing density (how close the individual solid-statelight sources 101 can be placed to each other) is disadvantageous andlimits the number of solid-state light sources 101 that can be used. Insuch embodiments, a means for condensing the light emitted by thesolid-state light sources 101 into a smaller area can be advantageous.Means for efficient condensing of the light and coupling to the SamplingSubsystem 200 are discussed in subsequent paragraphs.

In some embodiments, an alternative to the planar array of individualsolid-state light sources is employed. An example of an individualsolid-state light source 101, a laser diode, is shown in FIG. 6 and iscomprised of the semiconductor chip 103 and a laser emission aperture104.

In another embodiment, a cumulative number of individual solid-statelight sources 101 are divided into one or more groups. Each solid-statelight source 101 within the one or more groups is mounted onto a commoncarrier 105 (one carrier per group) with a predefined spacing betweenthe other solid-state light sources 101. This approach is referred to asa light source “carrier” 104 and is depicted in FIG. 7. The carrier 105may be formed, for example, from ceramic. In this embodiment, differentwavelengths can come from different sources, for example, differentwafers that are diced into laser chips. Multiple laser chips may form asolid-state light source 101. This allows multiple wavelengths to beaccommodated by combining lasers from several sources (wafers, differentvendors, etc.). The advantages of this approach are a fewer number ofsolid-state light source assemblies and a known relationship ofsolid-state light source locations relative to each other. This in turnallows the potential for a reduced number of temperature controlledpackages relative to controlling individual solid-state light sources.Furthermore, as the solid-state light sources within the package are infixed and known locations relative to each other, more efficient lightcoupling approaches are enabled.

In other embodiments, multiple solid-state light sources are locatedwithin the same physical semiconductor in order to further reduce thenumber of parts in the illumination/modulation subsystem 100. In suchembodiments, the solid-state light sources 101 within a semiconductorcan be the same wavelength, different wavelengths, or a combinationthereof. When the solid-state light sources 101 are laser diodes orother solid state lasers, these embodiments are referred to as “laserbars” 106. Similar to the carrier embodiments, an advantage of the laserbar 106 is the very well characterized and specified locations of eachsolid-state light source 101. Overall, the laser bar 106 results in asignificant reduction in the number of individual semiconductors, thetotal number of system components, and therefore subsystem complexityand cost.

Multiple solid-state light sources 101 of the same wavelength can beused to increase optical power at that wavelength. In some embodiments,solid-state light sources 101 of the same wavelength are adjacent to,and very near each other in order to allow efficient light coupling.FIG. 8 shows a laser bar 106 comprised of 12 groups of 2 laser diodes(24 total laser emitters). The two lasers forming a pair 107 have acommon wavelength and each pair 107 has a different wavelength than theother pairs (12 distinct wavelengths across the bar 106 in thisembodiment). Each pair 107 is spaced 480 microns from adjacent pairs 107and the spacing between the two emitters 101 of a pair 107 is 5 microns.In embodiments employing DFB diode lasers, the different wavelengths areachieved using a single semiconductor chip by applying gratings withdifferent pitches to each pair 107. The emission of DFB lasers isgenerally single mode, which is advantageous in some embodiments. Oneskilled in the art recognizes the large number of permutations of totalsolid-state light sources 101 and their wavelengths of emission that areencompassed by the carrier 105 and bar embodiments 106. The embodimentsdisclosed herein are not intended to be limiting to the scope of thepresent invention.

In some embodiments, dedicated thermoelectric coolers for each emittercan be cost and size prohibitive and a single global cooler ortemperature control may not provide sufficient local temperaturecontrol. In such cases, local temperature control within a semiconductorcan be achieved using a local heating provision near the solid-statelight source. An embodiment of the heating provision is a local resistornear the solid-state light source what allows applied current to beconverted into local heat. This approach allows a single temperaturecontrol provision to apply the majority of the heating/cooling loadwhile the local provisions allow fine tuning for each solid-state lightsource. This allows both a higher degree of stability as well as theability to tune emission wavelengths of each laser by changing the localtemperature.

Strategies for Efficient Coupling of Solid-State Light Sources to theSampling Subsystem

Whether the solid-state light sources of an embodiment reside inindividual packages or are grouped onto a smaller number of carriers orbars, the density of the solid-state light source emission apertures isnot ideal as there is always a finite distance between neighboringsolid-state light sources. This spacing can, for example, be driven bythe sizes of the individual solid-state light source packages as well asthe need to allow for a finite spacing to dissipate heat. In someembodiments of the present invention, the density of the emissionapertures is not a concern and the output of the individual solid-statelight sources can be collected, combined, and homogenized using a lighthomogenizer whose cross section is sufficiently large to encompass allsolid-state light source emission apertures in theIllumination/Modulation Subsystem 100. However, in this case the photonflux at the output of the light homogenizer is lower than ideal as thelight from the solid-state light sources has been substantiallyuniformly distributed across the entire area of the cross section. Thiscorresponds to a reduction in the etendue of the system, which can bedisadvantageous in some embodiments.

In embodiments where the reduction in etendue should be minimized, thereare multiple strategies for more efficiently combining the outputs ofthe individual solid-state light source emission apertures. Several ofthe embodiments of the present invention incorporate optical fibers 108as a means for collecting light from a solid-state light source 101 or apair of solid-state light sources 107 and combining it with the lightcollected from the other solid-state light sources 101 or pairs ofsolid-state light sources 107 in the system (see FIG. 9). A plurality ofindividual optical fibers 108 may be bundled into a cable 109. In oneembodiment, illustrated in FIG. 13, a fiber 108 collects light from eachof the twelve solid-state light sources 101 or pairs of solid-statelight sources 107. The twelve fibers 108 can be bundled into a cable109. The emission apertures of many solid-state light sources can be onthe order of a few microns in diameter. Some of the embodiments of thepresent invention can use large core multi-mode optical fiber (incontrast to small core, single mode fibers often used intelecommunications). The large fiber diameter relative to the smalldiameter of the emission aperture allows for an optical fiber to collectthe light from an emission aperture with an alignment tolerance of tensof microns in all dimensions. Depending on the spacing of emissionapertures and the size of the optical fiber 108, light from more thanone aperture can be collected by a given optical fiber (see FIG. 9).

The advantage of such an approach is that it allows the outputs of anynumber of solid-state light sources to be combined by using anequivalent or smaller number of optical fibers. The opposing ends of theoptical fibers can then be combined into a bundle. In some embodiments,the bundle is a circular hex-pack. For a given number of fibers of agiven diameter, this configuration represents the smallestcross-sectional area and thus maintains the greatest photon flux andetendue. Furthermore, the optical fibers allow linear or other geometricarrangements of solid-state light sources (e.g. such as laser bars) tobe fabricated while retaining the ability to combine their outputs intoa small area aperture which allows for efficient coupling of thecollected light to the Sampling Subsystem 200. A laser bar assembly maycomprise a laser bar 106, ceramic carrier 105 with electrical contacts,an optical fiber coupler (not illustrated), a copper micro bench (notillustrated), and a thermo electric cooler (not illustrated). Theassembly can be housed in a hermetically sealed package such as anindustry standard butterfly package. In some embodiments, a lighthomogenizer can be placed at the output of the bundle of optical fibersin order to spatially and/or angularly homogenize the outputs of theindividual optical fibers. In such embodiments, the cross sectional areacan be matched to the area of the bundle of optical fibers in order tominimize any reduction in photon flux and etendue. In some embodiments,the arrangement of optical fibers at the output bundle can be matched tothe cross section of the light homogenizer (e.g. square, hexagonal,etc.).

Fiber optic coupling approaches also allow multiple assemblies withsolid-state light source apertures to be combined into a single outputaperture. For example, FIG. 10 shows 4 laser bars 106, each with 12pairs of laser emitters 107 (see FIG. 8). A multimode optical fiber 110is used to collect the light from each emitter pair 107 (48 total fibers108). The opposing ends of the 48 fibers 108 are then combined into acircular hex pack output ferrule 111.

Methods and Apparatuses for Homogenization of Illumination/ModulationSubsystem Output

Light homogenizers 112 such as optical diffusers, light pipes, and otherscramblers can be incorporated into some embodiments of theillumination/modulation subsystem 100 in order to provide reproducibleand, preferably, uniform radiance at the input of the tissue samplingsubsystem 200. FIG. 11 shows an example light homogenizer 112 comprisinga ground glass diffuser and hexagonal cross section light pipe with 2opposing bends. Uniform radiance can ensure good photometric accuracyand even illumination of the tissue. Uniform radiance can also reduceerrors associated with manufacturing differences between solid-statelight sources. Uniform radiance can be utilized in various embodimentsof the present invention for achieving accurate and precisemeasurements. See, e.g., U.S. Pat. No. 6,684,099, incorporated herein byreference.

A ground glass plate is an example of an optical diffuser. The groundsurface of the plate effectively scrambles the angle of the radiationemanating from the solid-state light source and its transfer optics. Alight pipe can be used to homogenize the intensity of the radiation suchthat it is spatially uniform at the output of the light pipe. Inaddition, light pipes with a double bend will scramble the angles of theradiation. For creation of uniform spatial intensity and angulardistribution, the cross section of the light pipe should not becircular. Square, hexagonal and octagonal cross sections are effectivescrambling geometries. The output of the light pipe can directly coupleto the input of the tissue sampler or can be used in conjunction withadditional transfer optics before the light is sent to the tissuesampler. See, e.g., U.S. patent application Ser. No. 09/832,586,“Illumination Device and Method for Spectroscopic Analysis,”incorporated herein by reference.

Sampling Subsystem

FIG. 1 indicates that the orientation of the tissue sampling subsystem200 is between the illumination/modulation (100) and data acquisition(300) subsystems. Referring to FIG. 1, the tissue sampling subsystem 200introduces radiation generated by the illumination/modulation subsystem100 into the sample (e.g. tissue of the subject, collects a portion ofthe radiation that is not absorbed by the sample and sends thatradiation to the optical detector in the data acquisition subsystem 300for measurement. FIGS. 12 through 17 depict elements of an exampletissue sampling subsystem 200. Referring to FIG. 12, the tissue samplingsubsystem 200 has an optical input 202, a sampling surface 204 whichforms a tissue interface 206 that interrogates the tissue and an opticaloutput 207. The subsystem further includes an ergonomic apparatus 210,depicted in FIG. 13, which holds the sampling surface 204 and positionsthe tissue at the interface 206. An output 211 sends a signal to aprocessing circuit, which may be, for example, a microprocessor. In anexemplary subsystem, a device that thermostats the tissue interface isincluded and, in some embodiments In other embodiments, an indexmatching fluid can be used to improve the optical interface between thetissue and sampling surface. The improved interface can reduce error andincrease the efficiency, thereby improving the net attribute signal.See, e.g. U.S. Pat. Nos. 6,622,032, 6,152,876, 5,823,951, and 5,655,530,each of which is incorporated herein by reference.

The optical input 202 of the tissue sampling subsystem 200 receivesradiation from the illumination/modulation subsystem 100 (e.g., lightexiting a light pipe) and transfers that radiation to the tissueinterface 206. As an example, the optical input can comprise a bundle ofoptical fibers that are arranged in a geometric pattern that collects anappropriate amount of light from the illumination/modulation subsystem.FIG. 14 depicts one example arrangement. The plan view depicts the endsof the input and output fibers in a geometry at the sampling surfaceincluding six clusters 208 arranged in a circular pattern. Each clusterincludes four central output fibers 212 which collect diffuselyreflected light from the tissue. Around each grouping of four centraloutput fibers 212 is a cylinder of material 215 which ensures about a100 μm gap between the edges of the central output fibers 212 and theinner ring of input fibers 214. The 100 μm gap can be important tomeasuring ethanol in the dermis. As shown in FIG. 14, two concentricrings of input fibers 214 are arranged around the cylinder of material215. As shown in one example embodiment, 32 input fibers surround fouroutput fibers.

FIG. 15 demonstrates an alternative to cluster geometries for thesampling subsystem. In this embodiment, the illumination and collectionfiber optics are arranged in a linear geometry. Each row can be eitherfor illumination or light collection and can be of any length suitableto achieve sufficient signal to noise. In addition, the number of rowscan be 2 or more in order to alter the physical area covered by thesampling subsystem. The total number of potential illumination fibers isdependent on the physical size of emissive area of the solid-state lightsource subsystem (e.g. the area of the cross section of the fiber bundleor light homogenizer depending on the embodiment) and the area of eachfiber. In some embodiments, multiple solid-state light source subsystemscan be used to increase the number of illumination fibers. If the numberof collection fibers results in an area larger than the photodetector ofthe Data Acquisition Subsystem (300), a light pipe or other homogenizerfollowed by an aperture can be used to reduce the size of the outputarea of the sampling subsystem. The purpose of the light pipe or otherhomogenizer is to ensure that each collection fiber contributessubstantially equally to the light that passes through the aperture. Insome embodiments, the light homogenizer can be omitted and the apertureused by itself. In other embodiments, the detector active area serves asthe aperture (e.g. there is no distinct aperture). In this case, lightthat is not incident to the active area is effectively vignetted.

In some embodiments of the Sampling Subsystem (200) of the presentinvention, the portion of the optical probe that interacts with thesample can be comprised of a stack of two or more linear ribbons ofoptical fibers. These arrangements allow the size and shape of theoptical probe interface to be designed appropriately for the sample andmeasurement location (e.g. hand, finger) of interest. FIG. 16 shows anexample embodiment of a sampling subsystem based on a linear stack offribbons. Additional details regarding suitable embodiments for use inthe present invention can be found in co-pending U.S. patent applicationSer. Nos. 12/185,217 and 12/185,224, each of which is incorporatedherein by reference.

In many embodiments of tissue analyte measurement devices, thephotodetector is the limiting aperture of the system. In such systems,the throughput (and correspondingly the signal to noise ratio, SNR) ofthe system could be optimized by incorporating an optical probe designthat illuminates a larger area of the sample (tissue) while collectinglight from a smaller aperture that is consistent with the solid angle ofacceptance of the photodetector. Referring to the optical probe designin FIG. 16, each collection fiber (black circles) is surrounded by 8illumination fibers (white circles). For each collection fiber, thisgeometric difference in area allows each of the 8 illumination fibers tocontribute to the light collected. The net effect of this approach isthat it allows more light to be collected from the blackbody lightsource and delivered to the sample without being vignetted by thelimiting aperture. This can be advantageous for light sources thatinherently have large emissive areas (such as many blackbody emitters).

However, the photon flux of semiconductor light sources such as diodelasers can be much higher than that of blackbody light sources. As aresult, a limited number of semiconductor light sources can deliverequivalent or superior photon flux with a smaller solid angle relativeto their blackbody counter parts. This can result in the solid angle ofthe photon emission (the combined solid angles of all semiconductorlight sources) being smaller than the solid angle of acceptance of thedetector. In other words, the light source, rather than thephotodetector, is the effective limiting aperture of the system. In suchcases, optical probe designs such as those shown in FIG. 16 do notoptimize the throughput and SNR of the systems. While such opticalprobes are suitable in some embodiments of the present invention,alternative designs can be preferable. In other embodiments, the numberof illumination optical fibers may be less than or equal to the numberof collection optical fibers. These optical probe designs have samplingsurfaces that allow a small illumination area consistent with thesmaller area of solid-state light source emission with a largercollection area consistent with the larger area of the photodetector. Asa result, the overall efficiency of the system is improved.

The sampling subsystems can also use one or more channels, where achannel refers to a specific orientation of the illumination andcollection fibers. An orientation is comprised of the angle of theillumination fiber or fibers, the angle of the collection fiber orfibers, the numerical aperture of the illumination fiber or fibers, thenumerical aperture of the collection fiber or fibers, and the separationdistance between the illumination and collection fiber or fibers.Multiple channels can be used in conjunction, either simultaneously orserially, to improve the accuracy of the noninvasive measurements. In onembodiment, a two channel sampling subsystem is utilized. In thisexample, the two channels are measuring the same tissue structure.Therefore each channel provides a measurement of the same tissue from adifferent perspective. The second perspective helps to provideadditional spectroscopic information that helps to decouple the signalsdue to scattering and absorption. Referring to FIG. 17, the group offibers (1 source, 1 receiver #1, and 1 receiver #2 in this example) canbe replicated 1 to N times in order to increase the sampler area andimprove optical efficiency. Each of the fibers can have a differentnumerical aperture and angle (θ). The distances between fibers, X and Y,determine the source-receiver separation. Furthermore, an additionalsource channel can be added that creates a 4-channel sampling subsystem.One skilled in the art recognizes the large number of possible variantson the number and relationship between channels.

In an experiment in which a multiple channel sampler was used fornoninvasive glucose measurements, the results indicated that thecombination of the two channels provides superior measurement accuracywhen compared to either channel individually. While this example usestwo channels, additional channels can provide additional informationthat can further improve the measurement.

Another aspect of a multiple channel sampling subsystem is the abilityto improve detection and mitigation of topical interferents, such assweat or lotion, present on the sample. FIG. 17 is a diagram of themultiple channel sampling subsystem in the presence of a topicalinterferent. FIG. 17 shows the sampling subsystem at the tissueinterface, a layer of topical interferent, and the tissue. In thisexample the contribution to each channel's measurement due to thetopical interferent is identical. This allows the potential to decouplethe common topical interferent signal present in both channels from thetissue signal that will be different for the two channels.

Referring to FIG. 12, the clustered input and output fibers are mountedinto a cluster ferrule that is mounted into a sampling head 216. Thesampling head 216 includes the sampling surface 204 that is polishedflat to allow formation of a good tissue interface. Likewise, the inputfibers are clustered into a ferrule 218 connected at the input ends tointerface with the illumination/modulation subsystem 100. The outputends of the output fibers are clustered into a ferrule 220 for interfacewith the data acquisition subsystem 300.

Alternatively, the optical input can use a combination of light pipes,refractive and/or reflective optics to transfer input light to thetissue interface. It is important that the input optics of the tissuesampling subsystem collect sufficient light from theillumination/modulation subsystem 100 in order to achieve an acceptablenet attribute signal.

The tissue interface irradiates the tissue in a manner that targets thecompartments of the tissue pertinent to the attribute of interest, andcan discriminate against light that does not travel a significantdistance through those compartments. As an example, a 100-μm gap betweenillumination and collection optical fibers can discriminate againstlight that contains little attribute information. In addition, thetissue interface can average over a certain area of the tissue to reduceerrors due to the heterogeneous nature of the tissue. The tissuesampling interface can reject specular and short pathlength rays and itcan collect the portion of the light that travels the desired pathlengththrough the tissue with high efficiency in order to maximize the netattribute signal of the system. The tissue sampling interface can employoptical fibers to channel the light from the input to the tissue in apredetermined geometry as discussed above. The optical fibers can bearranged in pattern that targets certain layers of the tissue thatcontain good attribute information.

The spacing, angle, numerical aperture, and placement of the input andoutput fibers can be arranged in a manner to achieve effective depthtargeting. In addition to the use of optical fibers, the tissue samplinginterface can use a non-fiber based arrangement that places a pattern ofinput and output areas on the surface of the tissue. Proper masking ofthe non-fiber based tissue sampling interface ensures that the inputlight travels a minimum distance in the tissue and contains validattribute information. Finally, the tissue sampling interface can bethermostatted to control the temperature of the tissue in apredetermined fashion. The temperature of the tissue sampling interfacecan be set such that prediction errors due to temperature variation arereduced. Further, reference errors are reduced when building acalibration model. These methods are disclosed in U.S. patentapplication Ser. No. 09/343,800, entitled “Method and Apparatus forNon-Invasive Blood Analyte Measurement with Fluid CompartmentEquilibration,” which is incorporated herein by reference.

The tissue sampling subsystem 200 can employ an ergonomic apparatus orguide 213 that positions the tissue over the sampling interface 204 in areproducible manner. An example ergonomic apparatus 213 that guides thefinger reproducibly to the sampling surface is depicted in FIG. 13. Theergonomic apparatus 213 includes a base 217 having an opening 219 therethrough. The opening 219 is sized for receiving the sample head 216therein to position the sampling surface 204 generally coplanar with anupper surface of the base. Careful attention must be given to theergonomics of the tissue sampling interface or significant samplingerror can result. Alternate sites, for example the tops or palmar sideof fingertips or the forearm can also be accommodated using variationsof the systems described herein.

The output of the tissue sampling subsystem 200 transfers the portion ofthe light not absorbed by the tissue that has traveled an acceptablepath through the tissue to the optical detector in the data acquisitionsubsystem 300. The output of the tissue sampling subsystem 200 can useany combination of refractive and/or reflective optics to focus theoutput light onto the optical detector. In some embodiments, thecollected light is homogenized (see U.S. Pat. No. 6,684,099, Apparatusand Methods for Reducing Spectral Complexity in Optical Sampling,incorporated herein by reference) in order to mitigate for spatial andangular effects that might be sample dependent.

Data Acquisition Subsystem

The data acquisition subsystem 300 converts the optical signal from thesampling subsystem into a digital representation. FIG. 18 is a schematicrepresentation of the data acquisition subsystem 300. An advantage of atleast one embodiment of the present invention is that, similar to aninterferometric spectrometer, only a single element detector is requiredto measure all desired wavelengths. Array detectors and their supportingelectronics are a significant drawback due to their expensive nature.

The optical detector converts the incident light into an electricalsignal as a function of time. Examples of detectors that are sensitivein the spectral range of 1.0 to 2.5 m include InGaAs, InAs, InSb, Ge,PbS, and PbSe. An example embodiment of the present invention canutilize a 1-mm, thermo-electrically cooled, extended range InGaAsdetector that is sensitive to light in the 1.0 to 2.5 μm range. The 2.5μm, extended range InGaAs detector has low Johnson noise and, as aresult, allows Shot noise limited performance for the photon fluxemanating from the tissue sampling subsystem. The extended InGaAsdetector has peak sensitivity in the 2.0 to 2.5 μm spectral region wherethree very important alcohol absorption features are located. Incomparison with the liquid nitrogen cooled InSb detector, thethermo-electrically cooled, extended range InGaAs can be more practicalfor a commercial product. Also, this detector exhibits over 120 dbc oflinearity in the 1.0 to 2.5 μm spectral region. Alternative detectorscan be suitable if the alcohol measurement system utilizes alternativewavelength regions. For example, a silicon detector can be suitable ifthe wavelength range of interest were within the 300-1100 nm range. Anyphotodetector can be used as long as the given photodetector satisfiesbasic sensitivity, noise and speed requirements.

The remainder of the data acquisition subsystem 300 amplifies andfilters the electrical signal from the detector and then converts theresulting analog electrical signal to its digital representation with ananalog to digital converter, digital filtering, and re-sampling of thedigital signal from equal time spacing to equal position spacing. Theanalog electronics and ADC must support the high SNR and linearityinherent in the signal. To preserve the SNR and linearity of the signal,the data acquisition subsystem 300 can support at least 100 dbc of SNRplus distortion. The data acquisition subsystem 300 can produce adigitized representation of the signal. In some embodiments, a 24-bitdelta-sigma ADC can be operated at 96 or 192 kHz. In a system that hasonly one channel of signal to digitize (instead of the two more commonin delta-sigma ADC's), the signal can be passed into both inputs of theADC and averaged following digitization. This operation can help toreduce any uncorrelated noise introduced by the ADC. If systemperformance requirements permit, alternate analog to digital converterscan be used in which the sample acquisition is synchronized with thesolid-state light source modulation rather than captured at equal timeintervals. The digitized signal can be passed to a computing subsystem400 for further processing, as discussed below.

The constant time sampling data acquisition subsystem 300 has severaldistinct advantages over other methods of digitizing signals. Theseadvantages include greater dynamic range, lower noise, reduced spectralartifacts; detector noise limited operation and simpler and lessexpensive analog electronics. In addition, the constant time samplingtechnique allows digital compensation for frequency response distortionsintroduced by the analog electronics prior to the ADC. This includesnon-linear phase error in amplification and filtering circuits as wellas the non-ideal frequency response of the optical detector. Theuniformly sampled digital signal allows for the application of one ormore digital filters whose cumulative frequency response is the inverseof the analog electronics' transfer function (see, e.g., U.S. Pat. No.7,446,878, incorporated herein by reference).

Computing Subsystem 400

The computing subsystem 400 performs multiple functions such convertingthe digitized data obtained from the data acquisition subsystem 300 tointensity versus wavelength spectra, performing spectral outlier checkson the spectra, spectral preprocessing in preparation for determinationof the attribute of interest, determination of the attribute ofinterest, system status checks, display and processing requirementsassociated with the user interface, and data transfer and storage. Insome embodiments, the computing subsystem is contained in a dedicatedpersonal computer or laptop computer that is connected to the othersubsystems of the invention. In other embodiments, the computingsubsystem is a dedicated, embedded computer.

After converting the digitized data from the detector to intensityversus wavelength spectra, the computer system can check the spectra foroutliers or bad scans. An outlier sample or bad scan is one thatviolates the hypothesized relationship between the measured signal andthe properties of interest. Examples of outlier conditions includeconditions where the calibrated instrument is operated outside of thespecified operating ranges for ambient temperature, ambient humidity,vibration tolerance, component tolerance, power levels, etc. Inaddition, an outlier can occur if the composition or concentration ofthe sample is different than the composition or concentration range ofthe samples used to build the calibration model. The calibration modelwill be discussed later in this disclosure. Any outliers or bad scanscan be deleted and the remaining good spectra can be averaged togetherto produce an average single beam spectrum for the measurement. Theintensity spectra can be converted to absorbance by taking the negativebase 10 logarithm (−log 10) of the spectrum. The absorbance spectrum canbe scaled to renormalize the noise.

A scaled absorbance spectrum can be used to determine the attribute ofinterest in conjunction with a calibration model that is obtained fromthe calibration subsystem 500. After determination of the attribute ofinterest, the computing subsystem 400 can report the result 830, e.g.,to the subject, to an operator or administrator, to a recording system,or to a remote monitor. The computing subsystem 400 can also report thelevel of confidence in the goodness of the result. If the confidencelevel is low, the computing subsystem 400 can withhold the result andask the subject to retest. If required, additional information can beconveyed that directs the user to perform a corrective action. See,e.g., US Application 20040204868, incorporated herein by reference. Theresults can be reported visually on a display, by audio and/or byprinted means. Additionally, the results can be stored to form ahistorical record of the attribute. In other embodiments, the resultscan be stored and transferred to a remote monitoring or storage facilityvia the internet, phone line, or cell phone service.

The computing subsystem 400 includes a central processing unit (CPU),memory, storage, a display and preferably a communication link. Anexample of a CPU is the Intel Pentium microprocessor. The memory can bestatic random access memory (RAM) and/or dynamic random access memory.The storage can be accomplished with non-volatile RAM or a disk drive. Aliquid crystal, LED, or other display can be suitable. The communicationlink can be, as examples, a high speed serial link, an Ethernet link, ora wireless communication link. The computer subsystem can, for example,produce attribute measurements from the received and processedinterferograms, perform calibration maintenance, perform calibrationtransfer, run instrument diagnostics, store a history of measuredalcohol concentrations and other pertinent information, and in someembodiments, communicate with remote hosts to send and receive data andnew software updates.

The computing system 400 can also contain a communication link thatallows transfer of a subject's alcohol measurement records and thecorresponding spectra to an external database. In addition, thecommunication link can be used to download new software to the computerand update the multivariate calibration model. The computer system canbe viewed as an information appliance. Examples of informationappliances include personal digital assistants, web-enabled cellularphones and handheld computers.

Calibration Subsystem 500

A calibration model is used in connection with the spectral informationin order to obtain alcohol measurements. In some embodiments, thecalibration model is formed by acquiring blood reference measurementsand contemporaneous spectroscopic data on multiple subjects in a widevariety of environmental conditions. In these embodiments, spectroscopicdata can be acquired from each subject over a range of blood alcoholconcentrations. In other embodiments, a hybrid calibration model can beto measure the alcohol concentrations of subject spectra. In this case,the term hybrid model denotes that a partial least squares (PLS)calibration model was developed using a combination of in vitro and invivo spectral data. The in vitro portion of the data was a 0.1 mmpathlength transmission spectrum of 500 mg/dL alcohol in water measuredusing the non-invasive measurement system configured for transmissionmeasurements. The transmission spectrum was ratioed to a 0.1 mmpathlength transmission spectrum of water, converted to absorbance, andnormalized to unit pathlength and concentration.

Light propagation through tissue is a complex function of the diffusereflectance optical tissue sampler design, physiological variables, andwavenumber. Consequently, the pathlength of light through tissue has awavenumber dependence that is not encountered in scatter-freetransmission measurements. In order to account for the wavenumberdependence, the interaction of the optical tissue sampler with thescattering properties of human tissue was modeled via Monte-Carlosimulation using a commercial optical ray-tracing software package(TracePro). Using the resulting model of the photon-tissue interactions,an estimate of the effective pathlength of light through the dermis andsubcutaneous tissue layers as a function of wavenumber was generated.The effective pathlength (l_(eff)) is defined as

${{l_{eff}(v)} = \frac{\sum\limits_{i = 1}^{N}\; {l_{i}{\exp \left( {{- {\mu_{a}(v)}}l_{i}} \right)}}}{\sum\limits_{i = 1}^{N}\; l_{i}}},$

where v is wavenumber, l_(i) is the pathlength traversed by the i^(th)ray in the Monte Carlo simulation [mm], N is the total number of rays inthe simulation, and a is the (wavenumber-dependent) absorptioncoefficient [mm⁻¹]. Due to its large absorption in vivo, water is theonly analyte that has a significant effect on the effective pathlength.Therefore, for the purposes of the effective pathlength calculation, theabsorption coefficients used were those of water at physiologicalconcentrations. The alcohol absorbance spectrum (as measured intransmission) was then scaled by the computed path function to form acorrected alcohol spectrum representative of the wavenumber dependentpathlength measured by the diffuse reflectance optical sampler. Thiscorrected spectrum formed the base spectrum for the mathematicaladdition of alcohol to the calibration spectra.

The in vivo data comprised noninvasive tissue spectra collected frompersons who had not consumed alcohol. A hybrid model was formed byadding the alcohol pure component spectrum, weighted by various alcohol“concentrations” (ranging from 0 to 160 mg/dL), to the noninvasivetissue spectral data. The PLS calibration model was built by regressingthe synthetic alcohol concentrations on the hybrid spectral data. FIG.19 is a schematic representation of a hybrid calibration formationprocess. The hybrid calibration in this work used approximately 1500non-invasive tissue spectra that were collected from 133 subjects overthree months.

The use of hybrid calibration models, rather than calibration modelsbuilt from spectra acquired from subjects who have consumed alcohol, canprovide significant advantages. The hybrid modeling process makes itpossible to generate calibration spectra that contain higherconcentrations (up to 160 mg/dL in this work) of alcohol than would beconsidered safe for consumption in a human subject study (120 mg/dL isconsidered a safe upper limit). This can result in a strongercalibration with a wider range of analyte concentrations that is able topredict higher alcohol concentrations more accurately. This can beimportant because alcohol concentrations observed in the field can bemore than double the maximum safe dosage in a clinical research setting.The hybrid calibration process also allows the prevention ofcorrelations between alcohol and the spectral interferents in tissue.For example, the random addition of alcohol signal to the calibrationspectra prevents alcohol concentration from being correlated with waterconcentration. Thus, the hybrid approach prevents the possibility thatthe measurement could spuriously track changes in tissue water contentinstead of alcohol concentration.

Once formed, it is desirable that a calibration remains stable andproduces accurate attribute predictions over an extended period of time.This process is referred to as calibration maintenance and can becomprised of multiple methods that can be used individually or inconjunction. The first method is to create the calibration in a mannerthat inherently makes it robust. Several different types of instrumentaland environmental variation can affect the prediction capability of acalibration model. It is possible and desirable to reduce the magnitudeof the effect of instrumental and environmental variation byincorporating this variation into the calibration model.

It is difficult, however, to span the entire possible range ofinstrument states during the calibration period. System perturbationscan result in the instrument being operated outside the space of thecalibration model. Measurements made while the instrument is in aninadequately modeled state can exhibit prediction errors. In the case ofin vivo optical measurements of medically significant attributes, thesetypes of errors can result in erroneous measurements that degrade theutility of the system. Therefore it is often advantageous to useadditional calibration maintenance techniques during the life of theinstrument in order to continually verify and correct for theinstrument's status.

Examples of problematic instrument and environmental variation include,but are not limited to: changes in the levels of environmentalinterferents such as water vapor or CO₂ gas, changes in the alignment ofthe instrument's optical components, fluctuations in the output power ofthe instrument's illumination system, and changes in the spatial andangular distribution of the light output by the instrument'sillumination system.

Calibration maintenance techniques are discussed in U.S. Pat. No.6,983,176, “Optically Similar Reference Samples and Related Methods forMultivariate Calibration Models Used in Optical Spectroscopy”; U.S. Pat.No. 7,092,832, “Adaptive Compensation for Measurement Distortions inSpectroscopy”; U.S. Pat. No. 7,098,037, “Accommodating Subject andInstrument Variations in Spectroscopic Determinations”, and U.S. Pat.No. 7,202,091, “Optically Similar Reference Samples”, each of which isincorporated herein by reference. In some of the disclosed methods, anenvironmentally inert non-tissue sample, such as an integrating sphere,that may or may not contain the attribute of interest is used in orderto monitor the instrument over time. The sample can be incorporated intothe optical path of the instrument or interface with the samplingsubsystem in a manner similar to that of tissue measurements. The samplecan be used in transmission or in reflectance and can contain stablespectral features or contribute no spectral features of its own. Thematerial can be a solid, liquid, or gel material as long as its spectrumis stable or predicable over time. Any unexplained change in the spectraacquired from the sample over time indicate that the instrument hasundergone a perturbation or drift due to environmental effects. Thespectral change can then be used to correct subsequent tissuemeasurements in humans in order to ensure and accurate attributemeasurement.

Another means for achieving successful calibration maintenance is toupdate the calibration using measurements acquired on the instrumentover time. Usually, knowledge of the reference value of the analyteproperty of interest is required in order to perform such an update.However, in some applications, it is known that the reference value isusually, but not always, a specific value. In this case, this knowledgecan be used to update the calibration even though the specific value ofthe analyte property is not known for each measurement. For example, inalcohol screening in residential treatment centers, the vast majority ofmeasurements are performed on individuals that have complied with theiralcohol consumption restrictions and therefore have an alcoholconcentration of zero. In this case, the alcohol concentrationmeasurement or the associated spectrum obtained from the devicedisclosed according to the various embodiments of the present inventioncan be used in conjunction with a presumed zero as a reference value.Thus, the calibration can be updated to include new information as it isacquired in the field. This approach can also be used to performcalibration transfer as measurements with presumed zeros can be used atthe time of system manufacture or installation in order to remove anysystem-specific bias in the analyte property measurements of interest.The calibration maintenance update or calibration transferimplementation can be accomplished by a variety of means such as, butnot limited to, orthogonal signal correction (OSV), orthogonal modelingtechniques, neural networks, inverse regression methods (PLS, PCR, MLR),direct regression methods (CLS), classification schemes, simple medianor moving windows, principal components analysis, or combinationsthereof.

Once a calibration is formed, it is often desirable to transfer thecalibration to all existing and future units. This process is commonlyreferred to as calibration transfer. While not required, calibrationtransfer prevents the need for a calibration to be determined on eachsystem that is manufactured. This represents a significant time and costsavings that can affect the difference between success or failure of acommercial product. Calibration transfer arises from the fact thatoptical and electronic components vary from unit to unit which, inaggregate, can result in a significant difference in spectra obtainedfrom multiple instruments. For example, two solid-state light sourcescan have different color temperatures thereby resulting in a differentlight distribution for the two sources. The responsivity of twodetectors can also differ significantly, which can result in additionalspectral differences.

Similar to calibration maintenance, multiple methods can be used inorder to effectively achieve calibration transfer. The first method isto build the calibration with multiple instruments. The presence ofmultiple instruments allows the spectral variation associated withinstrument differences to be determined and made orthogonal to theattribute signal during the calibration formation process. While thisapproach reduces the net attribute signal, it can be an effective meansof calibration transfer.

Additional calibration transfer methods involve explicitly determiningthe difference in the spectral signature of a system relative to thoseused to build the calibration. In this case, the spectral difference canthen be used to correct a spectral measurement prior to attributeprediction on a system or it can be used to correct the predictedattribute value directly. The spectral signature specific to aninstrument can be determined from the relative difference in spectra ofa stable sample acquired from the system of interest and those used tobuild the calibration. The samples described in the calibrationmaintenance section are also applicable to calibration transfer. See,e.g. U.S. Pat. No. 6,441,388, “Method and Apparatus for SpectroscopicCalibration Transfer”, incorporated herein by reference.

Alcohol Measurement Modalities

Depending on the application of interest, the measurement of an analyteproperty can be considered in terms of two modalities. The firstmodality is “walk up” or “universal” and represents an analyte propertydetermination wherein prior measurements of the sample (e.g. subject)are not used in determining the analyte property from the currentmeasurement of interest. In the case of measuring in vivo alcohol,driving under the influence enforcement would fall into this modality asin most cases the person being tested will not have been previouslymeasured on the alcohol measurement device. Thus, no prior knowledge ofthat person is available for use in the current determination of theanalyte property.

The second modality is termed “enrolled” or “tailored” and representssituations where prior measurements from the sample or subject areavailable for use in determining the analyte property of the currentmeasurement. An example of an environment where this modality can beapplied is vehicle interlocks where a limited number of people arepermitted to drive or operate a vehicle or machine. Additionalinformation regarding embodiments of enrolled and tailored applicationscan be found in U.S. Pat. Nos. 6,157,041 and 6,528,809, titled “Methodand Apparatus for Tailoring Spectroscopic Calibration Models”, each ofwhich is incorporated herein by reference. In enrolled applications, thecombination of the analyte property measurement with a biometricmeasurement can be particularly advantageous as the same spectroscopicmeasurement can assess if a prospective operator is authorized to usethe equipment or vehicle via the biometric while the analyte propertycan access their fitness level (e.g. sobriety).

Methods for Determining Biometric Verification or Identification fromSpectroscopic Signals

Biometric identification describes the process of using one or morephysical or behavioral features to identify a person or other biologicalentity. There are two common biometric modes: identification andverification. Biometric identification attempts to answer the questionof, “do I know you?” The biometric measurement device collects a set ofbiometric data from a target individual. From this information alone itassesses whether the person was previously enrolled in the biometricsystem. Systems that perform the biometric identification task, such asthe FBI's Automatic Fingerprint Identification System (AFIS), aregenerally very expensive (several million dollars or more) and requiremany minutes to detect a match between an unknown sample and a largedatabase containing hundreds of thousands or millions of entries. Inbiometric verification the relevant question is, “are you who you sayyou are?” This mode is used in cases where an individual makes a claimof identity using a code, magnetic card, or other means, and the deviceuses the biometric data to confirm the identity of the person bycomparing the target biometric data with the enrolled data thatcorresponds with the purported identity. The present apparatus andmethods for monitoring the presence or concentration of alcohol orsubstances of abuse in controlled environments can use either biometricmode.

There also exists at least one variant between these two modes that isalso suitable for use in various embodiments of the present invention.This variant occurs in the case where a small number of individuals arecontained in the enrolled database and the biometric applicationrequires the determination of only whether a target individual is amongthe enrolled set. In this case, the exact identity of the individual isnot required and thus the task is somewhat different (and often easier)than the identification task described above. This variant might beuseful in applications where the biometric system is used in methodswhere the tested individual must be both part of the authorized groupand sober but their specific identity is not required. The term“identity characteristic” includes all of the above modes, variants, andcombinations or variations thereof.

There are three major data elements associated with a biometricmeasurement: calibration, enrollment, and target spectral data. Thecalibration data are used to establish spectral features that areimportant for biometric determinations. This set of data consists ofseries of spectroscopic tissue measurements that are collected from anindividual or individuals of known identity. Preferably, these data arecollected over a period of time and a set of conditions such thatmultiple spectra are collected on each individual while they span nearlythe full range of physiological states that a person is expected to gothrough. In addition, the instrument or instruments used for spectralcollection generally should also span the full range of instrumental andenvironmental effects that it or sister instruments are likely to see inactual use. These calibration data are then analyzed in such a way as toestablish spectral wavelengths or “factors” (i.e. linear combinations ofwavelengths or spectral shapes) that are sensitive to between-personspectral differences while minimizing sensitivity to within-person,instrumental (both within- and between-instruments), and environmentaleffects. These wavelengths or factors are then used subsequently toperform the biometric determination tasks.

The second major set of spectral data used for biometric determinationsis the enrollment spectral data. The purpose of the enrollment spectrafor a given subject or individual is to generate a “representation” ofthat subject's unique spectroscopic characteristics. Enrollment spectraare collected from individuals who are authorized or otherwise requiredto be recognized by the biometric system. Each enrollment spectrum canbe collected over a period of seconds or minutes. Two or more enrollmentmeasurements can be collected from the individual to ensure similaritybetween the measurements and rule out one or more measurements ifartifacts are detected. If one or more measurements are discarded,additional enrollment spectra can be collected. The enrollmentmeasurements for a given subject can be averaged together, otherwisecombined, or stored separately. In any case, the data are stored in anenrollment database. In some cases, each set of enrollment data arelinked with an identifier (e.g. a password or key code) for the personson whom the spectra were measured. In the case of an identificationtask, the identifier can be used for record keeping purposes of whoaccessed the biometric system at which times. For a verification task,the identifier is used to extract the proper set of enrollment dataagainst which verification is performed.

The third and final major set of data used for the biometric system isthe spectral data collected when a person attempts to use the biometricsystem for identification or verification. These data are referred to astarget spectra. They are compared to the measurements stored in theenrollment database (or subset of the database in the case of identityverification) using the classification wavelengths or factors obtainedfrom the calibration set. In the case of biometric identification, thesystem compares the target spectrum to all of the enrollment spectra andreports a match if one or more of the enrolled individual's data issufficiently similar to the target spectrum. If more than one enrolledindividual matches the target, then either all of the matchingindividuals can be reported, or the best match can be reported as theidentified person. In the case of biometric verification, the targetspectrum is accompanied by an asserted identity that is collected usinga magnetic card, a typed user name or identifier, a transponder, asignal from another biometric system, or other means. The assertedidentity is then used to retrieve the corresponding set of spectral datafrom the enrollment database, against which the biometric similaritydetermination is made and the identity verified or denied. If thesimilarity is inadequate, then the biometric determination is cancelledand a new target measurement may be attempted.

In one method of verification, principle component analysis is appliedto the calibration data to generate spectral factors. These factors arethen applied to the spectral difference taken between a target spectrumand an enrollment spectrum to generate Mahalanobis distance and spectralresidual magnitude values as similarity metrics. Identify is verifiedonly if the aforementioned distance and magnitude are less than apredetermined threshold set for each. Similarly, in an example methodfor biometric identification, the Mahalanobis distance and spectralresidual magnitude are calculated for the target spectrum relative eachof the database spectra. The identity of the person providing the testspectrum is established as the person or persons associated with thedatabase measurement that gave the smallest Mahalanobis distance andspectral residual magnitude that is less than a predetermined thresholdset for each.

In an example method, the identification or verification task isimplemented when a person seeks to perform an operation for which thereare a limited number of people authorized (e.g., perform a spectroscopicmeasurement, enter a controlled facility, pass through an immigrationcheckpoint, etc.). The person's spectral data is used for identificationor verification of the person's identity. In this method, the personinitially enrolls in the system by collecting one or more representativetissue spectra. If two or more spectra are collected during theenrollment, then these spectra can be checked for consistency andrecorded only if they are sufficiently similar, limiting the possibilityof a sample artifact corrupting the enrollment data. For a verificationimplementation, an identifier such as a PIN code, magnetic card number,username, badge, voice pattern, other biometric, or some otheridentifier can also be collected and associated with the confirmedenrollment spectrum or spectra.

In subsequent use, biometric identification can take place by collectinga spectrum from a person attempting to gain authorization. This spectrumcan then be compared to the spectra in the enrolled authorizationdatabase and an identification made if the match to an authorizeddatabase entry was better than a predetermined threshold. Theverification task is similar, but can require that the person presentthe identifier in addition to a collected spectrum. The identifier canthen be used to select a particular enrollment database spectrum andauthorization can be granted if the current spectrum is sufficientlysimilar to the selected enrollment spectrum. If the biometric task isassociated with an operation for which only a single person isauthorized, then the verification task and identification task are thesame and both simplify to an assurance that the sole authorizedindividual is attempting the operation without the need for a separateidentifier.

The biometric measurement, regardless of mode, can be performed in avariety of ways including linear discriminant analysis, quadraticdiscriminant analysis, K-nearest neighbors, neural networks, and othermultivariate analysis techniques or classification techniques. Some ofthese methods rely upon establishing the underlying spectral shapes(factors, loading vectors, eigenvectors, latent variables, etc.) in theintra-person calibration database, and then using standard outliermethodologies (spectral F ratios, Mahalanobis distances, Euclideandistances, etc.) to determine the consistency of an incoming measurementwith the enrollment database. The underlying spectral shapes can begenerated by multiple means as disclosed herein.

First, the underlying spectral shapes can be generated based upon simplespectral decompositions (eigen analysis, Fourier analysis, etc.) of thecalibration data. The second method of generating underlying spectralshapes relates to the development of a generic model as described inU.S. Pat. No. 6,157,041, entitled “Methods and Apparatus for TailoringSpectroscopic Calibration Models,” which is incorporated by reference.In this application, the underlying spectral shapes are generatedthrough a calibration procedure performed on intra-person spectralfeatures. The underlying spectral shapes can be generated by thedevelopment of a calibration based upon simulated constituent variation.The simulated constituent variation can model the variation introducedby real physiological or environmental or instrumental variation or canbe simply be an artificial spectroscopic variation. It is recognizedthat other means of determining underlying shapes would be applicable tothe identification and verification methods of the disclosed embodimentsof the present invention. These methods can be used either inconjunction with, or in lieu of the aforementioned techniques.

Calibration Check Samples

In addition to disposables to ensure subject safety, disposablecalibration check samples can be used to verify that the instrument isin proper working condition. In many commercial applications of alcoholmeasurements, the status of the instrument must be verified to ensurethat subsequent measurements will provide accurate alcoholconcentrations or attribute estimates. The instrument status is oftenchecked immediately prior to a subject measurement. In some embodiments,the calibration check sample can include alcohol. In other embodiments,the check sample can be an environmentally stable and spectrally inertsample, such as an integrating sphere. The check sample can be a gas orliquid that is injected or flowed through a spectroscopic samplingchamber. The check sample can also be a solid, such as a gel, that maycontain alcohol. The check sample can be constructed to interface withthe sampling subsystem or it can be incorporated into another area ofthe optical path of the system. These examples are meant to beillustrative and are not limiting to the various possible calibrationcheck samples.

Direction of Change (DOC) and Rate of Change (ROC)

Methods for measurement of the direction and magnitude of concentrationchanges of tissue constituents, such as alcohol, using spectroscopy areconsidered to be within the scope of the present invention. Thenon-invasive measurement obtained from the current invention isinherently semi-time resolved. This allows attributes, such as alcoholconcentration, to be determined as a function of time. The time resolvedalcohol concentrations can then be used to determine the rate anddirection of change of the alcohol concentration. In addition, thedirection of change information can be used to partially compensate forany difference in blood and non-invasive alcohol concentration that iscaused by physiological kinetics. See U.S. Pat. No. 7,016,713,“Determination of Direction and Rate of Change of an Analyte”, and USApplication 20060167349, “Apparatus for Noninvasive Determination ofRate of Change of an Analyte”, each of which is incorporated herein byreference. A variety of techniques for enhancing the rate and directionsignal have been uncovered. Some of these techniques include heatingelements, rubrifractants, and index-matching media. The presentinvention is not limited to a particular form of enhancement orequilibration. These enhancements are not a required in the presentinvention, but are included for illustrative purposes only.

Subject Safety

Another aspect of non-invasive alcohol measurements is the safety of thesubjects during the measurements. In order to prevent measurementcontamination or transfer of pathogens between subjects it is desirable,but not necessary, to use disposable cleaning agents and/or protectivesurfaces in order to protect each subject and prevent fluid or pathogentransfer between subjects. For example, in some embodiments an isopropylwipe can be used to clean each subject's sampling site and/or thesampling subsystem surface prior to measurement. In other embodiments, adisposable thin film of material such as ACLAR could be placed betweenthe sampling subsystem and the subject prior to each measurement inorder to prevent physical contact between the subject and theinstrument. In other embodiments, both cleaning and a film could be usedsimultaneously. As mentioned in the sampling subsystem portion of thisdisclosure, the film can also be attached to a positioning device andthen applied to the subject's sampling site. In this embodiment, thepositioning device can interface with the sampling subsystem and preventthe subject from moving during the measurement while the film serves itsprotective role.

Topical Interferents

In subject measurements the presence of topical interferents on thesampling site is a significant concern. Many topical interferents havespectral signatures in the near infrared region and can thereforecontribute significant measurement error when present. Certainembodiments of the present invention deal with the potential for topicalinterferents in three ways that can be used individually or inconjunction. First, a disposable cleaning agent similar to thatdescribed in the subject safety section can be used. The use of thecleaning agent can either be at the discretion of the system operator ora mandatory step in the measurement process. Multiple cleaning agentscan also be used that individually target different types of topicalinterferents. For example, one cleaning agent can be used to removegrease and oils, while another could be used to remove consumer goodssuch as cologne or perfume. The purpose of the cleaning agents is toremove topical interferents prior to the attribute measurement in orderto prevent them from influencing the accuracy of the system.

The second method for mitigating the presence of topical interferents isto determine if one or more interferents are present on the samplingsite. The multivariate calibration models used in the calibrationsubsystem offer inherent outlier metrics that yield importantinformation regarding the presence of un-modeled interferents (topicalor otherwise). As a result, they provide insight into thetrustworthiness of the attribute measurement. FIG. 20 shows exampleoutlier metric values from noninvasive measurements acquired during theclinical studies. All of the large metric values (clearly separated fromthe majority of the points) correspond to measurements where grease hadbeen intentionally applied to the subject's sampling site. These metricsdo not specifically identify the cause of the outlier, but they doindicate that the associated attribute measurement is suspect. Aninflated outlier metric value (a value beyond a fixed threshold, forexample) can be used to trigger a fixed response such as a repeat of themeasurement, application of an alternative calibration model, or asampling site cleaning procedure. This is represented in FIG. 20 as the“Spectral Check OK” decision point.

The final topical interferent mitigation method involves adapting thecalibration model to include the spectral signature of the topicalinterferent. The adapted calibration model can either be created ondemand or selected from an existing library of calibration models. Eachcalibration in the library would be targeted at mitigating a differentinterferent or class of interferents such as oils. In some embodiments,the appropriate calibration model can be chosen based on the portion ofan acquired spectrum that is unexplained by the original calibrationmodel. This portion of the spectrum is referred to as the calibrationmodel residual. Because each topical interferent or class ofinterferents has a unique near infrared spectrum, the calibration modelresidual can be used to identify the topical interferent.

The model residual or the pure spectrum (obtained from a stored library)of the interferents can then be incorporated into the spectra used toform the calibration. The multivariate calibration is then reformed withthe new spectra such that the portion of the attribute signal that isorthogonal to the interferent can be determined. The new calibrationmodel is then used to measure the attribute of interest and therebyreduce the effects of the topical interferent on attribute measurementaccuracy. The resulting model will reduce the effect of the interferenton the alcohol measurement at the expense of measurement precision whenno interferents are present. This process is referred to as calibrationimmunization. The immunization process is similar to the hybridcalibration formation process shown in FIG. 19, but includes theadditional step of the mathematical addition of the interferent'sspectral variation. It should be noted that, due to the impact of theimmunization process on measurement precision, it can be desirable toidentify possible interferents for each measurement and immunizespecifically against them rather than attempt to develop a calibrationthat is immunized against all possible interferents. Additional detailscan be found in US 20070142720, “Apparatus and methods for mitigatingthe effects of foreign interferents on analyte measurements inspectroscopy”, incorporated herein by reference.

Advantages of Semiconductor Light Source Alternatives

Most light sources used in NIR and IR spectroscopy are blackbodyradiators. The light emitted by a blackbody radiator is governed byPlank's law which indicates that the intensity of the light emitted is afunction of wavelength and the temperature of the blackbody. FIG. 21shows normalized NIR spectra of 1300 and 3000 K blackbody radiators overthe 100-33000 cm⁻¹ (100-0.3 μm) range with the 4000-8000 cm⁻¹ (2.5-1.25μm) range used by the alcohol measurement device shaded. 1300 K is areasonable temperature for the ceramic-based blackbody light source and3000 K is a reasonable temperature for Quartz Tungsten Halogen (QTH)lamps which are often employed in spectroscopic applications. FIG. 21indicates that the optical efficiency of both blackbody light sources isnot ideal in that a significant amount of light is emitted atwavelengths outside the region of interest for measuring alcohol withthe optical efficiency of the ceramic light source being 58% and the QTHonly 18%.

In addition to optical efficiency, blackbody light sources can have poorelectrical efficiency. Practical blackbody light sources require asignificant amount of electrical power, not all of which is converted toemitted light. Electrical and optical power measurements on hundreds ofceramic blackbody light sources that show an average of 1.1 W of opticalpower at an average of 24 W of electrical power (4.4% electricalefficiency). When combined with the optical efficiency of 58%, theoverall efficiency of the ceramic blackbody is approximately 2.5%. Inother words, at 24 W of electrical power, approximately 0.6 W of opticalpower is emitted in the 4000 to 8000 cm¹ region of interest. Furtherlosses are incurred as not all light emitted by the source is collectedby the remainder of the optical system.

As indicated by the low electrical efficiency, most of the appliedelectrical power is converted to heat which has a detrimental beyond thehigher than desired power requirement. The heat generated by theblackbody light source can have an impact on the thermal state andstability of the spectroscopic measurement device. Consequently, in somesituations the device must be powered on and allowed to reach thermalequilibrium prior to performing measurements. The equilibration timeassociated with the blackbody light source can range from minutes tohours which can be disadvantageous in some situations.

Blackbody light sources exhibit an aging effect as the materialresistance changes. From an optical perspective, there are tosignificant implications associated with the light source aging. First,as the resistance increases the amount of optical power emitteddecreases. In one experiment, the measured intensity over time observedfor a demonstrative ceramic blackbody light source exhibited a 50%reduction in power over 3500 hours. The intensity degradation over timetends to be exponential in nature and can necessitate replacement of thelight source at regular intervals which can be disadvantageous in somedeployment environments. Second, the temperature of the light sourcechanges which alters the distribution of the light as a function ofwavelength. Depending on the severity of the color temperature change,the stability of the spectroscopic device over time can be impacted.Solid-state light sources do not critically fail in any manner similarto filament lamps and have typical lifetimes ranging from 50,000 to100,000 hours. As a result, solid-state light sources offer thepotential for a 10× improvement in light source life and a correspondingreduction in the need for routine maintenance relative to blackbodylight sources.

Semiconductor light sources such as diode lasers can have small emissiveareas when compared to their blackbody counterparts that are driven bythe size of the semiconductor die itself. The photon emission cannotoccur outside of the area of the die as it is generated within thesemiconductor structure. The small size (a common emissive area is a 0.3mm×0.3 mm square or 0.09 mm²) can be advantageous in that anyheterogeneity within that area will be insignificant relative to size ofthe output of the illumination system (which can be several mm² orlarger depending on the application). Thus, as long as the die (or diesif multiple semiconductors are employed) do not physically move, thespatial output will be very stable. The objective of subsequent spatialhomogenizers is then to uniformly distribute the light emitted by thedie across the entire area of the illumination system output.

Another advantage of semiconductor light sources such as diode lasers,VCSEL's, and LED's is the ability to incorporate more than one dye intothe same physical package. For example, additional solid-state lightsources of the same type can be included in order to increase theoptical power at the corresponding wavelengths. Such approaches allow anunprecedented level of control over both the specific wavelengths andrelative intensities emitted by an illumination system. This could beused to accentuate wavelengths important to a given analyte of interestsuch as alcohol, while reducing the output at less-importantwavelengths. Whether the set of solid-state light sources is all of thesame type or a mixture, up to several hundred could be incorporated intothe same package while retaining an integrated optical area consistentwith use in noninvasive analyte measurements such as alcohol.

Another advantage of semiconductor light sources is the ability toselect which light sources are on at a given time as well as tune theiroutput via voltage or current and temperature. Consequently, a singleillumination system could be optimized for measurements of multipleanalytes. For example, when measuring alcohol in tissue a given set ofsolid-state light sources could be activated. Likewise, a different setcould be activated when measuring a different analyte such ascholesterol or glucose.

Methods for Spatial and Angular Homogenization

Light homogenizers such as optical diffusers, light pipes, and otherscramblers can be incorporated into some embodiments of theillumination/modulation subsystem 100 in order to provide reproducibleand, preferably, uniform radiance at the input of the tissue samplingsubsystem 200. Uniform radiance can ensure good photometric accuracy andeven illumination of the tissue. Uniform radiance can also reduce errorsassociated with manufacturing differences between solid-state lightsources. Uniform radiance can be utilized for achieving accurate andprecise measurements. See, e.g., U.S. Pat. No. 6,684,099, which isincorporated herein by reference.

A ground glass plate is an example of an optical diffuser. The groundsurface of the plate effectively scrambles the angle of the radiationemanating from the solid-state light source and its transfer optics. Alight pipe can be used to homogenize the intensity of the radiation suchthat it is spatially uniform at the output of the light pipe. Inaddition, light pipes with a double bend will scramble the angles of theradiation. For creation of uniform spatial intensity and angulardistribution, the cross section of the light pipe should not becircular. Square, hexagonal and octagonal cross sections are effectivescrambling geometries. The output of the light pipe can directly coupleto the input of the tissue sampler or can be used in conjunction withadditional transfer optics before the light is sent to the tissuesampler. See, e.g., U.S. patent application Ser. No. 09/832,586,“Illumination Device and Method for Spectroscopic Analysis,” which isincorporated herein by reference.

In an exemplary embodiment, the radiation homogenizer is a light pipe. Alight pipe is generally fabricated from a metallic, glass (amorphous),crystalline, polymeric, or other similar material, or any combinationthereof. Physically, the light pipe comprises a proximal end, a distalend, and a length there between. The length of a light pipe, for thisapplication, is measured by drawing a straight line from the proximalend to the distal end of the light pipe. Thus, the same segment of lightpipe 91 may have varying lengths depending upon the shape the segmentforms. The length of the segment readily varies with the light pipe'sintended application.

In an exemplary embodiment, the segment forms an S-shaped light pipe.The S-shaped bend in the light pipe provides angular homogenization ofthe light as it passes through the light pipe. It is, however,recognized that angular homogenization can be achieved in other ways. Aplurality of bends or a non-S-shaped bend could be used. Further, astraight light pipe could be used provided the interior surface of thelight pipe included a diffusely reflective coating over at least aportion of the length. The coating provides angular homogenization asthe light travels through the pipe. Alternatively, the interior surfaceof the light pipe can be modified to include dimples or“microstructures” such as micro-optical diffusers or lenses toaccomplish angular homogenization. Finally, a ground glass diffusercould be used to provide some angular homogenization.

The cross-section of the light pipe may also form various shapes. Inparticular, the cross-section of the light pipe is preferably polygonalin shape to provide spatial homogenization. Polygonal cross-sectionsinclude all polygonal forms having three to many sides. Certainpolygonal cross-sections are proven to improve spatial homogenization ofchanneled radiation. For example, a light pipe possessing a hexagonalcross-section the entire length thereof provided improved spatialhomogenization when compared to a light pipe with a cylindricalcross-section of the same length.

Additionally, cross-sections throughout the length of the light pipe mayvary. As such, the shape and diameter of any cross-section at one pointalong the length of the light pipe may vary with a second cross-sectiontaken at a second point along the same segment of pipe. In certainembodiments, the light pipe is of a hollow construction between the twoends. In these embodiments, at least one lumen or conduit may run thelength of the light pipe. The lumens of hollow light pipes generallypossess a reflective characteristic. This reflective characteristic aidsin channeling radiation through the length of the light pipe so that theradiation may be emitted at the pipe's distal end. The inner diameter ofthe lumen may further possess either a smooth, diffuse or a texturedsurface. The surface characteristics of the reflective lumen or conduitaid in spatially and angularly homogenizing radiation as it passesthrough the length of the light pipe.

In additional embodiments, the light pipe is of solid construction. Thesolid core could be cover plated, coated, or clad. Again, a solidconstruction light pipe generally provides for internal reflection. Thisinternal reflection allows radiation entering the proximal end of thesolid light pipe to be channeled through the length of the pipe. Thechanneled radiation may then be emitted out of the distal end of thepipe without significant loss of radiation intensity.

The faceted elliptical reflector is an example of an embodiment of thepresent invention which produces only part of the desiredcharacteristics in the output radiation. In the case of the facetedreflector, spatial homogenization is achieved but not angularhomogenization. In other cases, such as passing the output of thestandard system through ground glass, angular homogenization is achievedbut not spatial homogenization. In embodiments such as these, where onlyangular or spatial homogenization is produced (but not both) someimprovement in the performance of the spectroscopic system may beexpected. However, the degree of improvement would not be expected to beas great as for systems where spatial and angular homogenization of theradiation are simultaneously achieved.

Another method for creating both angular and spatial homogenization isto use an integrating sphere in the illumination system. Although commonto use an integrating sphere for detection of light, especially fromsamples that scatter light, integrating spheres have not been used aspart of the illumination system when seeking to measure analytesnoninvasively. In practice, radiation output from the emitter could becoupled into the integrating sphere with subsequent illumination of thetissue through an exit port. The emitter could also be located in theintegrating sphere. An integrating sphere will result in exceptionalangular and spatial homogenization but the efficiency of this system issignificantly less than other embodiments previously specified.

It is also recognized that other modifications can be made to thepresent disclosed system to accomplish desired homogenization of light.For example, the solid-state light source could be placed inside thelight pipe in a sealed arrangement which would eliminate the need forthe reflector. Further, the light pipe could be replaced by anintegrator, wherein the source is placed within the integrator. Further,the present system could be used in non-infrared applications to achievesimilar results in different wavelength regions depending upon the typeof analysis to be conducted.

DESCRIPTION OF EXAMPLE EMBODIMENTS

In an example embodiment of the present invention (schematicallydepicted in FIG. 22), a noninvasive alcohol measurement system iscomprised of 13 diode lasers that are used to measure 22 discretewavelengths. Table 1 shows a list of each diode lasers and theassociated target peak wavelengths that will be interrogated during thecourse of the measurement.

TABLE 1 Light Source # Wavelengths Measured (cm⁻¹) 1 4196.35, 4227.2  24288.91, 4304.34 3 4319.77, 4335.20 4 4350.62 5 4381.48, 4412.34 64443.19, 4474.05 7 4535.76, 4566.61 8 4597.47, 4612.90 9 4643.75 104674.61, 4690.04 11 4767.17 12 4828.88 13 4875.17, 4906.02

In this embodiment, each diode lasers is stabilized to a constanttemperature. The peak wavelength of each diode lasers is controlledbased on the circuit shown in FIG. 5 (each diode lasers having its owncircuit), which also enables the diode lasers to be turned On and Off.The specific state (On/Off) of each diode lasers at a given time duringa measurement is determined by a predetermined Hadamard or similarencoding matrix. In example embodiments incorporating solid-state lightsources, the Hadamard matrix is a pattern of On/Off states versus timefor each diode lasers that is stored in software and implemented inelectronics rather than a physical mask or chopper that wouldmechanically modulate the solid-state light sources. This allows theOn/Off states stored in software to be conveyed to the electroniccontrol circuits of each diode lasers during the measurement.

As several of the diode lasers in Table 1 are responsible for 2wavelength locations, a Hadamard scheme that incorporates allwavelengths can be difficult to achieve. In this case, a combination ofscanning and Hadamard encoding can allow all target wavelengths to bemeasured. In the present embodiment, all diode lasers are tuned to their1^(st) target wavelength (for those with more than 1 target wavelength)and a Hadamard encoding scheme used to achieve the associated multiplexbenefit. The diode lasers can then be tuned to their second targetwavelength and a 2^(nd) Hadamard encoding scheme used. Diode lasers withonly 1 target wavelength can be measured in either or both groups ordivided among the groups.

Furthermore, the groups can be interleaved in time. For example, for a 2second measurement, the first group can be measured for the 1^(st)second and the 2^(nd) group for the 2^(nd) second. Alternatively, themeasurement can alternate at 0.5 second intervals for 2 seconds. Themeasurement times do not need to be symmetric across the groups. Forexample, it can be desirable to optimize signal to noise ratio byweighting the measurement time towards one or the other group. Oneskilled in the art recognizes that many permutations of measurementtime, balancing the number of groups, balancing the ratio of scanning toHadamard, and interleaving are possible and contemplated in theembodiments of the present invention.

In the example embodiment, the output of each diode lasers is combinedand homogenized using a hexagonal cross-sectioned light pipe. In someembodiments, the light pipe can contain one or more bends in order toprovide angular homogenization in addition to spatial homogenization.Regardless, at the output of the light pipe, the emission of all diodelasers is preferably spatially and angularly homogenized such that allwavelengths have substantially equivalent spatial and angular contentupon introduction to the input of the sampling subsystem 200.

The homogenized light is introduced to the input of an optical probe. Inthe example embodiment, the input is comprised of 225, 0.37 NAsilica-silica optical fibers (referred to as illumination fibers)arranged in a geometry consistent with the cross section of the lighthomogenizer. The light is then transferred to the sample interface. Thelight exits the optical probe and enters the sample, a portion of thatlight interacts with the sample and is collected by 64 collectionfibers. In an exemplary embodiment, the collection fibers are 0.37 NAsilica-silica fibers.

The optical probe output arranges the collection fibers into a geometryconsistent with the introduction to a homogenizer. For the exampleembodiment, the homogenizer is a hexagonal light pipe. The homogenizerensures that the content of each collection fiber contributessubstantially equally to the measured optical signal. This can beimportant for samples, such as human tissue, that can be heterogeneousin nature. The output of the homogenizer is then focused onto an opticaldetector. In an exemplary embodiment, the optical detector is anextended InGaAs diode whose output current varies based upon the amountof incident light.

The processing subsystem then filters and processes the current and thenconverts it to a digital signal using a 2 channel delta-sigma ADC. Inthe example embodiment, the processed analog detector signal is dividedand introduced to both ADC channels. As the example embodiment involvesVCSEL's with 2 measurement groups (e.g. 2 target wavelengths), aHadamard transform is applied to the spectroscopic signal obtained fromeach group and the subsequent transforms combined to form an intensityspectrum. The intensity spectrum is then base 10 log transformed priorto subsequent alcohol concentration determination.

The example embodiment is suitable for either “enrolled” or“walk-up/universal” modalities as well as applications combining alcoholwith other analyte properties such as substances of abuse. Furthermore,any of the discussed modalities or combinations can be consideredindependently or combined with the measurement of a biometric property.

3,245 alcohol measurements were obtained from 89 people on 5 noninvasivealcohol systems that measured spectra incorporating 22 wavelengths inthe “walk-up” modality. The measurements spanned a wide range ofdemographic and environmental. FIG. 23 shows the near-infraredspectroscopic measurements obtained from the study. FIG. 24 comparesnoninvasive alcohol concentrations obtained from the spectroscopicmeasurements shown in FIG. 23 to contemporaneous capillary blood alcoholconcentration (BAC) alcohol.

Another example embodiment is shown in FIG. 39 and uses 39 wavelengthsmeasured using 39 diode lasers. Table 2 shows the diode lasers and theirtarget wavelengths.

TABLE 2 Target Wavelengths for Laser Diodes 4242.63 5708.27 4258.065739.12 4273.49 5816.26 4288.91 5831.69 4304.34 5862.54 4319.77 5877.974335.20 5908.83 4350.62 5924.25 4381.48 5955.11 4396.91 5970.54 4412.346016.82 4443.19 6047.68 4474.05 6078.53 4504.90 6124.82 4520.33 6155.674566.61 6186.53 4582.04 6263.67 4628.32 6356.23 4659.18 6402.52 4674.614705.46

The remainder of the system parameters including the sampling subsystem,light homogenizers, detector, and processing is identical to the earlierdescribed embodiment. FIG. 25 shows the 8,999 spectroscopic measurementsobtained from 134 people on 6 noninvasive measurement devices. FIG. 26shows the resulting noninvasive alcohol measurements relative to venousblood alcohol.

In some example embodiments, calibration transfer can be performed usinga small number of measurements on samples with known analyte properties.In the case of noninvasive alcohol measurements, each instrument canhave a small number of measurements performed on individuals with noalcohol present. Any non-zero alcohol result on the instrumenttranslates into a measurement error that can be used to correctsubsequent measurements on that instrument. The number of measurementsused to estimate the correction can vary and generally depends on therequired accuracy of the correction. In general, this process isanalogous to an instrument specific calibration consistent with alcoholdevices, such as breath testers, that are calibrated individually.

A similar approach can be applied to calibration maintenance. In manyapplications of alcohol testing, the majority of measurements areperformed on individuals where alcohol is unlikely to be present. Forexample in workplace safety where employees are routinely tested foralcohol, it is much more likely that an employee will be alcohol freethan intoxicated (e.g. most people enter the workplace alcohol-free). Inthis case, the true alcohol concentration can be assumed to be zero anda median or other means for excluding the infrequent, true alcoholevents could be used to estimate an instruments correction. This canimplemented as a running median filter, a moving window, or moresophisticated multivariate algorithm for determining the appropriatecorrection at a given time.

Those skilled in the art will recognize that the present invention canbe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail can be made without departing from the scope and spirit of thepresent invention.

On Going System Calibration

In order to maintain maximum accuracy and precision across operatingconditions and time, it is desirable to have information about the stateof the alcohol measurement devices (e.g. the optical and electricalcomponents that contribute to the measurement) just prior to tissuemeasurement. This is referred to as a “calibration measurement”. Whilecontrols related to current and temperature are employed for certainsensitive components of the system, there are a significant number ofmechanical and optical error contributors that may change with time andtemperature. In addition, even with controls in place, there can beerror associated with the operation of the electrical components as wellas factors related to the surface treatment, and possible lightcontamination, of the probe that also need to be considered. Therefore,it is desirable to measure the complete optical and electrical status ofthe device against a known standard sample just prior to measuring thetissue sample of interest. The measurement of the standard sample thenallows subsequent (or preceding) tissue measurements to be corrected forthe current status of the alcohol measurement device.

To obtain a calibration measurement, light from the lightsource/modulation subsystem (100) is delivered to the standard sample bythe sampling subsystem (200) where it interacts with the standardsample. A portion of the light is collected by the sampling subsystem(200) and coupled to the photodetector in the data acquisition subsystem(300). One way to achieve this is with optical fibers distinct fromthose of the sampling surface (e.g. the surface where skin tissue ismeasured). In this case, the light delivered to the standard samplewould travel a different optical path than the light that interrogatesskin. This difference in optical path can be acceptable in someembodiments. Furthermore, in other embodiments, the optical fibersthemselves can serve as the standard sample (e.g. the optical fiberscollect light from the light source/modulation subsystem (100) anddeliver it directly to the photodetector in the data acquisitionsubsystem (300). In some embodiments of these approaches a gatingmechanism can be applied that selects which optical path (the path tothe skin sampling surface or the path to the calibration sample) isbeing measured by the photodetector at a given time. While theseapproaches are acceptable in some embodiments, they are not optimal inthe sense that a different path from the actual probe is measured.

Therefore, in order to maintain substantially the same optical paths forlight interrogating skin tissue and the calibration standard a method isrequired to place a movable calibration standard with knowncharacteristics at the tissue interface of the sampling subsystem (200).The calibration sample can be measured shortly prior to tissuemeasurement and then removed for actual measurement. While thecalibration sample can be manually inserted into the path, an automaticmethod for insertion and removal is preferred in some embodiments.

One such method for automatic insertion of the calibration sample is tobuild it into the probe head cover or a button that the user interactswith. The main elements of such a method would be:

-   1) A movable door in close proximity to the tissue interface onto    which a reflective standard surface is added to the back-   2) A method for moving the door out of the way to present a tissue    measurement surface directly to the probe-   3) A method to return the reflective surface to a rest position

It should be noted that one skilled in the art may design any number ofelectromechanical or mechanical mechanisms to accomplish this purpose.

In the first embodiment, movable door, is coated on the underside withsuitable reflecting material and slides, allowing sensing head to rotateup to a finger surface. The spring provides a return force necessary toreturn to the rest/calibration position.

In the second embodiment, a sliding button acts as a guide for semiflexible tape which is fixed at the bottom end. The back of the flexibletape is coated with a suitable reflective surface. Movement of thesliding button allows the tape to slide below the window opening on theface of the button allowing sensor to come in contact with the finger.The spring provides return force necessary to return to therest/calibration condition. It should be noted that alternativeembodiments can be designed such that the sensing head is stationarywhile the door/button and/or calibration sample are the only movingparts.

It should be further noted that the embodiments can be enhanced withstyling features and finger guides to help facilitate placement withoutchanging the basic concept, and that the mechanism and additionalstyling features would work equally well whether the dorsal side of thefinger, palmer side of the finger, or other skin surface is presented.

Referring to FIG. 28, the system depicted in FIG. 1 can be incorporatedinto the starting system of any transport vehicle (including all formsof ground, water and air travel). For example, the system can beincorporated as an electromechanical component of an ignition systemincluding a starter button, key turn or other typically used form of adriver initiating power to prepare the transport vehicle for travel.

Such a system can be utilized to measure the presence or concentrationof an analyte or biometric identifier in a person attempting to startthe transport vehicle where the measured information is used to alterthe subsequent electromechanical response of the vehicle. For example, abiometric identification may be used to identify a specific driver (froma pool of possible drivers) and modify the position or orientation ofthe driver and/or control settings such as infotainment settings orvehicle actuator settings. In another example, as illustrated in FIG.27, the system can be used to measure the concentration of an analyte toeither enable/or disable the ability to start the transport vehicleand/or initiate an alternative action. For example, measurement ofalcohol in a vehicle driver above the legal threshold may restrict theability to start the transport vehicle, but also trigger a telematicssystem to provide an automated call to alternative forms of travelincluding designated drivers and/or taxis.

In another embodiment, the system can be integrated in a transportvehicle control system which is continuously or nearly continuously incontact with the operator such as a steering wheel, handle bars or yoke.As such, the system can continuously or periodically; or triggered byother control logic make analyte and/or biometric measurements which areused to affect the subsequent transport vehicle operation or trigger analternative action.

In another embodiment, the system can be integrated into a transportvehicle or facility access system (e.g. entry door, trunk, . . . ) andthus make analyte and/or biometric measurement which are used to affectthe access into and/or subsequent levels of control upon entry.

In another embodiment, the system can be incorporated into othertransport vehicle subsystems where direct contact between the operatorskin and the sampling sub-system 200 is temporarily, periodically orconstantly is maintained. A slightly modified embodiment wheresemi-passive contact is maintained and an embodiment where contact ismade through an operator initiated action are also possible. In suchcases, continuous or periodic analyte and/or biometric measurements canbe made which effect the subsequent transport vehicle operation ortrigger an alternative action.

In the case of the system described in FIG. 28, the human machineinteraction between the operator and the sampling sub-system 200 can beconfigured to inform the intended operator of the existence of thesystem and intended body part and/or location which must be coupled withthe sampling sub-system to trigger a measurement. For example, the useof audible sounds and/or speech and/or lighting and or haptic feedbackcan be used to educate the operator, provide positive/negative feedbackon the proper measurement process and/or the results of the measurement.

In an example embodiment of the present invention (schematicallydepicted in FIG. 29a-b ), differs from the system depicted in FIG. 22,by directly coupling discrete solid-state light sources of varyingwavelength into a homogenizer consisting of a material which minimizesthe losses across all supported wavelengths thus reducing the need for acoupling mechanism between the solid-state light source and thehomogenizer and the sensing sub-system. In this embodiment, thehomogenizer material, size, shape, coating can be controlled to optimizelight transmission and minimize losses while directly providing thesensor sub-system 200 emitter.

FIG. 7 depicts a system where multiple distinct emitters are used; in analternative embodiment depicted in FIG. 30, a single emitter can becreated with several grating zones with distinct current paths whichwhen driven with current in combinations product distinct wavelengths.By time varying which grating combinations are driven, distinctwavelengths can be achieved in a time domain signal. In such a way, amultitude of wavelengths can be sampled in time in a pre-determinedpattern. Knowledge of the sampling sequence in the detector andprocessor can be used to obtain the spectroscopy measurements describedin subsequent embodiments.

In another embodiment, the system further includes one or moreatmospheric, temperature and relative humidity sensors where themeasurements derived from these sensors are available to the sub-system400 to correct for and/or improve on the analyte and/or biometricmeasurements to correct for human variation due to these environmentaleffects and/or individual sub-system variations due to an extendedsystem (for example, where the measurement sub-system 200 is spatiallyor thermally distinct from sub-system 100; or where the system emittersand detectors are temperature compensated to a fixed value (independentof ambient conditions), but the fiberoptics, homogenizer and couplersrequire temperature compensation based on ambient conditions.

In the case of making some analyte measurements where the probability ofthe presence of the analyte in the pool of potential operators is low,it may be favorable to make a faster and simpler measurement to firstdetermine if any analyte is apparent, and only if detected, then make asubsequent measurement for the concentration of the analyte. This isdepicted in FIG. 31. For example, in the case of alcohol as an analyte,the majority of prospective vehicle operators will not have the presenceof alcohol in their system when attempting to start the vehicle. Apresence measurement can be used to decrease the average measurementtime.

In many safety applications, at least two disparate technology sensorsmust detect a signal to make a decision to actuate a countermeasure.This vastly reduces the propensity for false positives due to undetectedsingle sensor failure or errors. In a similar context, the systemdescribed in FIG. 32 can be coupled to include one or more independentsensors to indicate the presence or concentration of an analyte and/orconfirm a biometric measurement.

The system in FIG. 22 describes a system utilizing discrete wavelengthsolid-state light sources; an alternative embodiment depicted in FIG. 33depicts a system which utilizes a single wide spectrum black body sourcecoupled to discrete wavelength filters which only pass the intendedwavelengths. The subsequent processing steps remain the same as thoseindicated previously; however, undesirable system noise can be avoidedin the detection and discrimination process.

For system embodiments described previously which utilize diode lasers,the rise and fall characteristics of those devices can very in adeterministic fashion based on the driver and compensation circuits andalso the ambient temperature and electromechanical properties of thedevice itself (for example, the laser grating structures, materials,size, shape and heating/cooling components). As illustrated in FIG. 34,waiting until the solid-state light source intensity has settled to adesirable level (T2), may reduce the modulation time. In order toimprove the modulation rates available for multi-plexing lights ofvarying wavelength, the a-priori rise/fall properties can be compensatedfor in the detector logic thus reducing the settling time (T1).

It is to be understood that both the foregoing general description anddetailed description are exemplary and explanatory only, and are notrestrictive of the invention.

For purposes of this disclosure, the term “coupled” means the joining oftwo components (electrical or mechanical) directly or indirectly to oneanother. Such joining may be stationary in nature or movable in nature.Such joining may be achieved with the two components (electrical ormechanical) and any additional intermediate members being integrallyformed as a single unitary body with one another or with the twocomponents or the two components and any additional member beingattached to one another. Such joining may be permanent in nature oralternatively may be removable or releasable in nature.

The construction and arrangement of the diffuser as shown in thepreferred and other exemplary embodiments is illustrative only. Althoughonly a few embodiments of the present airbag assembly have beendescribed in detail in this disclosure, those skilled in the art whoreview this disclosure will readily appreciate that many modificationsare possible (e.g. variations in sizes, dimensions, structures, shapesand proportions of the various elements, values of parameters, mountingarrangements, use of materials, orientations, etc.) without materiallydeparting from the novel teachings and advantages of the subject matterrecited in this disclosure. Accordingly, all such modificationsattainable by one versed in the art from the present disclosure withinthe scope and spirit of the present invention are to be included asfurther embodiments of the present invention. The order or sequence ofany process or method steps may be varied or re-sequenced according toalternative embodiments. Other substitutions, modifications, changes andomissions may be made in the design, operating conditions andarrangement of the preferred and other exemplary embodiments withoutdeparting from the spirit of the present application.

1-25. (canceled)
 26. A system for non-invasively measuring an analyte ina vehicle driver and controlling a vehicle based on a measurement of theanalyte, the system comprising: a laser bar comprising at least twolaser diodes located on a single semiconductor in a linear array, afirst laser diode of the at least two laser diodes configured to emit afirst wavelength of light and a second laser diode of the at least twolaser diodes configured to emit a second wavelength of light; a sampledevice configured to introduce the first wavelength of light and thesecond wavelength of light into a tissue of the vehicle driver; anoptical detector configured to detect a first portion of the firstwavelength of light and a second portion of the second wavelength oflight that are not absorbed by the tissue of the vehicle driver; and acontroller configured to: calculate a measurement of the analyte in thetissue of the vehicle driver based on the first portion and the secondportion detected by the optical detector, determine whether themeasurement of the analyte in the tissue of the vehicle driver exceeds apre-determined value, and provide a signal to a device configured tocontrol the vehicle in response to determining that the measurement ofthe analyte does not exceed the pre-determined value.